Pyrazolopyridine Derivates

ABSTRACT

New compounds of formula (I) and the salts thereof, wherein the meanings for the various substituents are as disclosed in the description, are useful as p38 kinase inhibitors.

FIELD OF THE INVENTION

The present invention relates to a new series of pyrazolopyridinederivatives, a process to prepare them, pharmaceutical compositionscontaining these compounds and their application in medicine.

BACKGROUND OF THE INVENTION

Kinases are proteins involved in different cellular responses toexternal signals. In the Nineties, a new family of kinases called MAPK(mitogen-activated protein kinases) was discovered. MAPK activate theirsubstrates by phosphorylation in serine and threonine residues.

MAPK are activated by other kinases in response to a wide range ofsignals including growth factors, pro-inflammatory cytokines, UVradiation, endotoxins and osmotic stress. Once they are activated, MAPKactivate by phosphorylation other kinases or proteins, such astranscription factors, which, ultimately, induce an increase or adecrease in expression of a specific gene or group of genes.

The MAPK family includes kinases such as p38, ERK(extracellular-regulated protein kinase) and JNK (C-Jun N-terminalkinase).

Kinase p38 plays a crucial role in cellular response to stress and inthe activation pathway in the synthesis of numerous cytokines,especially tumor necrosis factor (TNF-α), interleukin-1 (IL-1),interleukin-6 (IL-6) and interleukin-8 (IL-8).

IL-1 and TNF-α are produced by macrophages and monocytes and areinvolved in the mediation of immunoregulation processes and otherphysiopathological conditions. For example, elevated levels of TNF-α areassociated with inflammatory and autoimmune diseases and with processesthat trigger the degradation of connective and bone tissue such asrheumatoid arthritis, osteoarthritis, diabetes, inflammatory boweldisease and sepsis.

Thus, p38 kinase inhibitors could be useful to treat or prevent diseasesmediated by cytokines such as IL-1 and TNF-α, as mentioned previously.

On the other hand, it has also been found that p38 inhibitors inhibitother pro-inflammatory proteins such as IL-6, IL-8, interferon-γ andGM-CSF (granulocyte-macrophage colony-stimulating factor). Moreover, inrecent studies it has been found that p38 inhibitors not only blockcytokine synthesis but also the cascade of signals that these induce,such as induction of the cyclooxygenase-2 enzyme (COX-2).

DESCRIPTION OF THE INVENTION

One aspect of the present invention relates to the new compounds ofgeneral formula I

wherein:A represents N or N⁺O⁻;R¹ represents phenyl or Het optionally substituted with one or moresubstituents selected from R^(a) and R^(b);R² represents Het optionally substituted with one or more substituentsselected from R^(a) and R^(b);R³ represents H, Cy optionally substituted with one or more substituentsselected from R^(a) and R^(b), or R³ represents C₁₋₆alkyl optionallysubstituted with one or more substituents selected from R^(b) and Cy*,wherein Cy* can be optionally substituted with one or more substituentsselected from R^(b) and R^(c);R⁴ represents H, R^(a), halogen, —OR^(a)′, —OCOR^(a), —OSO₂R^(a),—OCONR^(a)R^(a′), —NO₂, —CN, —COR^(a)′, —CO₂R^(a)′, —CONR^(a′)R^(a′),—NR^(a′)R^(a)′, —NR^(a′)COR^(a′), —NR^(a′)CONR^(a′)R^(a)′,—NR^(a′)CO₂R^(a), —NR^(a′)SO₂R^(a), —SR^(a)′, —SOR^(a), —SO₂R^(a) or—SO₂NR^(a′)R^(a′);R⁵ can be placed on any of the 2 N of the pyrazole ring of formula I andrepresents H or R^(f);each R^(a) independently represents C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynylor Cy, wherein the groups C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl can beoptionally substituted with one or more substituents selected from R^(b)and Cy*, and wherein any of the groups Cy or Cy* can be optionallysubstituted with one or more substituents selected from R^(b) and R^(c);each R^(a′) independently represents H or R^(a);each R^(b) independently represents halogen, —OR^(c)′, —OCOR^(c),—OSO₂R^(c), —OCONR^(c)R^(c)′, —NO₂, —CN, —COR^(c)′, —CO₂R^(c)′,—CONR^(c′)R^(c)′, —CONR^(c′)NR^(c′)R^(c)′, —NR^(c′)R^(c)′,—NR^(c′)COR^(c)′, —NR^(c′)CONR^(c′)R^(c)′, —NR^(c′)CO₂R^(c),—NR^(c′)SO₂R^(c), —SR^(c)′, —SOR^(c), —SO₂R^(c), —SO₂NR^(c′)R^(c)′,—C(NR^(c′))NR^(c′)R^(c)′, —C(NSO₂NR^(c′)R^(c′))NR^(c′)R^(c)′,—C(NOR^(c′))R^(c)′, —C(NNR^(c′)R^(c′))R^(c)′,—NR^(c′)C(NR^(c′))NR^(c′)R^(c′) or —NR^(c′)C(NCN)NR^(c′)R^(c′);each R^(c) independently represents C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynylor Cy, wherein all these groups can be optionally substituted with oneor more substituents R^(d);each R^(c′) independently represents H or R^(c);each R^(d) independently represents halogen, R^(e), —OR^(e)′, —OCOR^(e),—OSO₂R^(e), —OCONR^(e)R^(e)′, —NO₂, —CN, —COR^(e)′, —CO₂R^(e)′,—CONR^(e′)R^(e)′, —CONR^(e′)NR^(e′)R^(e)′, —NR^(e′)R^(e)′,—NR^(e′)COR^(e)′, —NR^(e′)CONR^(e′)R^(e)′, —NR^(e′)CO₂R^(e),—NR^(e′)SO₂R^(e), —SR^(e)′, —SOR^(e), —SO₂R^(e), —SO₂NR^(e′)R^(e)′,—C(NR^(e′))NR^(e′)R^(e)′, —C(NSO₂NR^(e′)R^(e′))NR^(e′)R^(e)′,—C(NOR^(e′))R^(e)′, —C(NNR^(e′)R^(e′))R^(e)′,—NR^(e′)C(NR^(e′))NR^(e′)R^(e)′, —NR^(e′)C(NCN)NR^(e′)R^(e′) or Cyoptionally substituted with one or more substituents selected fromhalogen, R^(e), —OR^(e)′, —OCOR^(e), —OSO₂R^(e), —OCONR^(e)R^(e)′, —NO₂,—CN, —COR^(e)′, —CO₂R^(e)′, —CONR^(e′)R^(e)′, —CONR^(e′)NR^(e′)R^(e)′,—NR^(e′)R^(e)′, —NR^(e′)COR^(e)′, —NR^(e′)CONR^(e′)R^(e)′,—NR^(e′)CO₂R^(e), —NR^(e′)SO₂R^(e), —SR^(e)′, —SOR^(e), —SO₂R^(e),—SO₂NR^(e′)R^(e)′, —C(NR^(e′))NR^(e′)R^(e)′,—C(NSO₂NR^(e′)R^(e′))NR^(e′)R^(e)′, —C(NOR^(e′))R^(e)′,—C(NNR^(e′)R^(e′))R^(e)′, —NR^(e′)C(NR^(e′))NR^(e′)R^(e′) and—NR^(e′)C(NCN)NR^(e′)R^(e′);each R^(e) independently represents C₁₋₆alkyl or haloC₁₋₆alkyl;each R^(e′) independently represents H or R^(e);R^(f) represents C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or Cy, wherein thegroups C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl can be optionallysubstituted with one or more substituents selected from R^(g) and Cy*,and wherein any of the groups Cy or Cy* can be optionally substitutedwith one or more substituents selected from R^(g) and R^(a);each R^(g) independently represents halogen, —OR^(a)′, —OCOR^(a),—OSO₂R^(a), —OCONR^(a)R^(a)′, —NO₂, —CN, —COR^(a)′, —CO₂R^(a)′,—CONR^(a′)R^(a)′, —CONR^(a′)NR^(a′)R^(a)′, —NR^(a′)R^(a)′,—NR^(a′)COR^(a)′, —NR^(a′)CONR^(a′)R^(a)′, —NR^(a′)CO₂R^(a),—NR^(a′)SO₂R^(a), —SR^(a)′, —SOR^(a), —SO₂R^(a), —SO₂NR^(a′)R^(a)′,—C(NR^(a′))NR^(a′)R^(a)′, —C(NSO₂NR^(a′)R^(a′))NR^(a′)R^(a)′,—C(NOR^(a′))R^(a)′, —C(NNR^(a′)R^(a′))R^(a)′,—NR^(a′)C(NR^(a′))NR^(a′)R^(a′) or —NR^(a′)C(NCN)NR^(a′)R^(a′);Het in the above definitions represents pyridine, pyrazine, pyrimidine,pyridazine, 2(1H)-pyridone, 2(1H)-pyrazinone, 2(1H)-pyrimidinone or2(1H)-pyridazinone;Cy or Cy* in the above definitions represent a partially unsaturated,saturated or aromatic 3- to 7-membered monocyclic or 8- to 12-memberedbicyclic carbocyclic ring, which optionally contains from 1 to 4heteroatoms selected from N, S and O, which can optionally contain 1 or2 oxo groups when the ring is saturated or partially unsaturated, andwherein said ring or rings can be bonded to the rest of the moleculethrough a carbon or a nitrogen atom.

The present invention also relates to the addition salts of thecompounds of the invention as well as their solvates and prodrugs. Aprodrug is defined as any precursor of a compound of formula I that canbe transformed in vivo into a compound of formula I.

Some compounds of formula I can have chiral centres that can give riseto various stereoisomers. The present invention relates to each of thesestereoisomers and also mixtures thereof. Moreover, some of the compoundsof the present invention can show cis/trans isomers. The presentinvention relates to each of the geometric isomers and mixtures thereof.

The compounds of formula I are selective p38 kinase inhibitors.

Thus, another aspect of this invention relates to the pharmaceuticalcompositions which comprise an effective amount of a compound of formulaI or a pharmaceutically acceptable salt, solvate or prodrug thereof andone or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the manufacture of a medicament for the treatment orprevention of diseases mediated by p38.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the manufacture of a medicament for the treatment orprevention of diseases mediated by cytokines.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the manufacture of a medicament for the treatment orprevention of diseases mediated by TNF-α, IL-1, IL-6 and/or IL-8.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the manufacture of a medicament for the treatment orprevention of a disease selected from immune, autoimmune andinflammatory diseases, cardiovascular diseases, infectious diseases,bone resorption disorders, neurodegenerative diseases, proliferativediseases and processes associated with the induction ofcyclooxygenase-2.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the treatment or prevention of diseases mediated by p38.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the treatment or prevention of diseases mediated bycytokines.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the treatment or prevention of diseases mediated by TNF-α,IL-1, IL-6 and/or IL-8.

Another aspect of the present invention relates to the use of a compoundof formula I or a pharmaceutically acceptable salt, solvate or prodrugthereof for the treatment or prevention of a disease selected fromimmune, autoimmune and inflammatory diseases, cardiovascular diseases,infectious diseases, bone resorption disorders, neurodegenerativediseases, proliferative diseases and processes associated with theinduction of cyclooxygenase-2.

Another aspect of the present invention relates to a method of treatingor preventing diseases mediated by p38 in a subject in need thereof,especially a human being, which comprises administering to said subjecta therapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt, solvate or prodrug thereof.

Another aspect of the present invention relates to a method of treatingor preventing diseases mediated by cytokines in a subject in needthereof, especially a human being, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula I ora pharmaceutically acceptable salt, solvate or prodrug thereof.

Another aspect of the present invention relates to a method of treatingor preventing diseases mediated by TNF-α, IL-1, IL-6 and/or IL-8 in asubject in need thereof, especially a human being, which comprisesadministering to said subject a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt, solvate orprodrug thereof.

Another aspect of the present invention relates to a method of treatingor preventing a disease selected from immune, autoimmune andinflammatory diseases, cardiovascular diseases, infectious diseases,bone resorption disorders, neurodegenerative diseases, proliferativediseases and processes associated with the induction of cyclooxygenase-2in a subject in need thereof, especially a human being, which comprisesadministering to said subject a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt, solvate orprodrug thereof.

Another aspect of the present invention relates to a process for thepreparation of a compound of formula I, which comprises:

(a) reacting a ketone of formula IV

wherein R¹ and R² have the meaning described above, with anaminopyrazole of formula V and an aldehyde of formula VI

wherein R³, R⁴ and R⁵ have the meaning described above; or(b) when in a compound of formula I, R⁵ represents H and R³ has the samemeaning as R¹, reacting a ketone of formula IV or an enolate of formulaVII

wherein R¹ and R² have the meaning described above, with anaminopyrazole of formula Va

wherein R⁴ has the meaning described above; or(c) when in a compound of formula I R⁴ represents NH₂, treating acompound of formula XIX

wherein R¹, R² and R³ have the meaning described above, with a hydrazineof formula VIIIa

wherein R⁵ has the meaning described above; or(d) converting, in one or a plurality of steps, a compound of formula Iinto another compound of formula I; and(e) if desired, after the previous steps, reacting a compound of formulaI with a base or an acid to give the corresponding salt.

In the previous definitions, the term C₁₋₆alkyl, as a group or part of agroup, means a straight or branched alkyl chain which contains from 1 to6 carbon atoms. Examples include among others the groups methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl and hexyl.

A haloC₁₋₆alkyl group means a group resulting from the replacement ofone or more hydrogen atoms from a C₁₋₆alkyl group with one or morehalogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be thesame or different. Examples include, among others, trifluoromethyl,fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl,2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl,heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5-fluoropentyl and6-fluorohexyl.

The term C₂₋₆alkenyl, as a group or part of a group, means a straight orbranched alkyl chain which contains from 2 to 6 carbon atoms and thatalso contains one or more double bonds. Examples include, among others,the groups ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl,2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and5-hexenyl.

The term C₂₋₆alkynyl, as a group or part of a group, means a straight orbranched alkyl chain which contains from 2 to 6 carbon atoms and thatalso contains one or more triple bonds. Examples include the groupsethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1,3-butadiynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

An oxo group means a carbonyl group (—CO—).

A halogen radical means fluoro, chloro, bromo or iodo.

Het in the definitions of R¹ and R² means pyridine, pyrazine,pyrimidine, pyridazine, 2(1H)-pyridone, 2(1H)-pyrazinone,2(1H)-pyrimidinone or 2(1H)-pyridazinone. As mentioned previously, thesegroups can be optionally substituted with one or more substituentsselected from R^(a) and R^(b), which can be placed on any availableposition of the Het group, and can be bonded to the rest of the moleculevia any available carbon or nitrogen atom.

The term Cy or Cy*, as a group or part of a group, means a 3- to7-membered monocyclic carbocyclic group or an 8- to 12-membered bicycliccarbocyclic group which can be partially unsaturated, saturated oraromatic and which can optionally contain from 1 to 4 heteratomsselected from N, S and O. When the Cy or Cy* group is saturated orpartially unsaturated, it can optionally contain 1 or 2 oxo groups. TheCy or Cy* ring or rings can be substituted as mentioned in thedefinition of general formula I, these substituents being placed on anyavailable position, and can be bonded to the rest of the moleculethrough any available carbon or nitrogen atom. Examples of Cy or Cy*groups include, among others, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, aziridine, oxirane, oxetane, imidazolidine,isothiazolidine, isoxazolidine, oxazolidine, pyrazolidine, pyrrolidine,thiazolidine, dioxane, morpholine, piperazine, piperidine, pyran,tetrahydropyran, azepine, oxazine, oxazoline, pyrroline, thiazoline,pyrazoline, imidazoline, isoxazoline, isothiazoline, phenyl, naphthyl,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-oxadiazole,1,3,4-thiadiazole, furan, imidazole, isoxazole, isothiazole, oxazole,pyrazole, pyrrole, thiazole, thiophene, 1,2,3-triazole, 1,2,4-triazole,pyrazine, pyridazine, pyridine, pyrimidine, benzimidazole, benzofuran,benzothiazole, benzothiophene, imidazopyrazine, imidazopyridazine,imidazopyridine, imidazopyrimidine, indazole, indole, isoindole,isoquinoline, tetrahydroisoquinoline, naphthyridine, pyrazolopyrazine,pyrazolopyridine, pyrazolopyrimidine, purine, quinazoline, quinoline,quinoxaline, cyclobutanone, cyclopentanone, cyclohexanone,cycloheptanone, pyrrolidin-2-one, piperidin-2-one, piperidin-4-one,2(1H)-pyridone, 2(1H)-pyrazinone, 2(1H)-pyrimidinone, 2(1H)-pyridazinoneand phthalimide.

The term heteroaryl, as a group or part of a group, means an aromatic 5-or 6-membered monocyclic or 8- to 12-membered bicyclic ring whichcontains from 1 to 4 heteroatoms selected from N, S and O and which canbe optionally substituted as disclosed whenever this term is used,wherein said substituents can be placed on any available position. Theheteroaryl group can be bonded to the rest of the molecule through anyavailable carbon or nitrogen atom. Examples of heteroaryl groups includeamong others 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-oxadiazole,1,3,4-thiadiazole, furan, imidazole, isoxazole, isothiazole, oxazole,pyrazole, pyrrole, thiazole, thiophene, 1,2,3-triazole, 1,2,4-triazole,pyrazine, pyridazine, pyridine, pyrimidine, benzimidazole, benzofuran,benzothiazole, benzothiophene, imidazopyrazine, imidazopyridazine,imidazopyridine, imidazopyrimidine, indazole, indole, isoindole,isoquinoline, naphthridine, pyrazolopyrazine, pyrazolopyridine,pyrazolopyrimidine, purine, quinazoline, quinoline and quinoxaline.

In the previous definitions of Het, heteroaryl, Cy and Cy*, the term ismeant to be the radical derived from the corresponding cycle.

In the previous definitions of heteroaryl, Cy and Cy*, when thespecified examples refer to a bicycle in general terms, all possibledispositions of the atoms are included. For example, the termpyrazolopyridine is to be understood as including groups such as1H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridine,1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[4,3-c]pyridine and1H-pyrazolo[4,3-b]pyridine; the term imidazopyrazine is to be understoodas including groups such as 1H-imidazo[4,5-b]pyrazine,imidazo[1,2-a]pyrazine and imidazo[1,5-a]pyrazine and the termpyrazolopyrimidine is to be understood as including groups such as1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[4,3-d]pyrimidine,pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-c]pyrimidine.

The expression “optionally substituted with one or more” means that agroup can be substituted with one or more, preferably with 1, 2, 3 or 4substituents, provided that this group has 1, 2, 3 or 4 positionssusceptible of being substituted.

In the previous definitions, when it is mentioned that R⁵ can be placedon any one of the 2N of the pyrazole ring this means that R⁵ can beplaced on the N at position 1 of the ring or on the N at position 2.Thus, the compounds of formula I include the following two types ofcompounds:

An embodiment of the invention are those compounds of formula I asdefined above wherein A represents N.

Another embodiment of the invention are the compounds of formula Iwherein A represents N and R⁵ can be placed on any of the 2 N of thepyrazole ring of formula I and represents H or R^(a).

Another embodiment of the invention are the compounds of formula Iwherein when R³ and R⁵ both represent H and R² represents Het optionallysubstituted with one or more substituents selected from halogen, —CN,—CF₃, —OH, —NO₂, —OR⁶, —NR⁶R⁶, —OCF₃, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl and Cy, wherein Cy can be optionally substituted with one ormore substituents selected from R^(b) and R^(c), and wherein R⁶represents C₁₋₆alkyl, then R⁴ is not —NR^(a′)COR^(a), —NHCONHR^(a) or—NHCO₂R^(a).

Another embodiment of the invention are the compounds of formula Iwherein when R³ and R⁵ both represent H, then R⁴ is not —NR^(a′)COR^(a),—NHCONHR^(a) or —NHCO₂R^(a).

Another embodiment of the invention are the compounds of formula Iwherein A represents N; R⁴ represents H, R^(a), halogen, —OR^(a)′,—OCOR^(a), —OSO₂R^(a), —OCONR^(a)R^(a)′, —NO₂, —CN, —COR^(a)′,—CO₂R^(a)′, —CONR^(a′)R^(a)′, —NR^(a′)R^(a)′, —NR^(a′)SO₂R^(a),—SR^(a)′, —SOR^(a), —SO₂R^(a) or —SO₂NR^(a′)R^(a′); and R⁵ can be placedon any of the 2 N of the pyrazole ring of formula I and represents H orR^(a).

Another embodiment of the invention are the compounds of formula Iwherein R¹ represents pyridine or phenyl, wherein all these groups canbe optionally substituted with one or more substituents selected fromR^(a) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R¹ represents phenyl optionally substituted with one or moresubstituents selected from R^(a) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R¹ represents phenyl optionally substituted with one or moresubstituents selected from halogen, —OR^(c)′, —NO₂, —CN,—CONR^(c′)R^(c)′, —NR^(c′)R^(c′) and C₁₋₆alkyl optionally substitutedwith one or more substituents selected from halogen, —OR^(c)′,—COR^(c)′, —NR^(c′)R^(c′) and —NR^(c′)COR^(c′).

Another embodiment of the invention are the compounds of formula Iwherein R¹ represents phenyl optionally substituted with one or moresubstituents selected from halogen and haloC₁₋₆alkyl.

Another embodiment of the invention are the compounds of formula Iwherein R² represents pyridine or pyrimidine, wherein all these groupscan be optionally substituted with one or more substituents selectedfrom R^(a) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R² represents 4-pyridine or 4-pyrimidine, wherein all thesegroups can be optionally substituted with one or more substituentsselected from R^(a) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R² represents 4-pyridine or 4-pyrimidine, wherein all thesegroups can be optionally substituted with one or more substituentsselected from halogen, —OR^(c)′, —NR^(c′)R^(c)′, —SR^(c′) and —SO₂R^(c).

Another embodiment of the invention are the compounds of formula Iwherein R² represents 4-pyridine.

Another embodiment of the invention are the compounds of formula Iwherein R² represents 4-pyrimidine substituted with —NR^(c′)R^(c)′,wherein in R²:

each R^(c′) independently represents H or R^(c);each R^(c) independently represents C₁₋₆alkyl optionally substitutedwith one or more substituents selected from Cy and —OR^(e′); andeach R^(e′) independently represents H or R^(e).

Another embodiment of the invention are the compounds of formula Iwherein R³ represents H or Cy optionally substituted with one or moresubstituents selected from R^(a) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R³ represents H, heteroaryl or phenyl, wherein all these groupscan be optionally substituted with one or more substituents selectedfrom R^(a) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R³ represents heteroaryl or phenyl, wherein all these groups canbe optionally substituted with one or more substituents selected fromR^(a′) and R^(b).

Another embodiment of the invention are the compounds of formula Iwherein R³ represents monocyclic heteroaryl or phenyl, wherein all thesegroups can be optionally substituted with one or more substituentsselected from halogen, —NO₂, —OR^(c)′, C₁₋₆alkyl and Cy, whereinC₁₋₆alkyl can be optionally substituted with one or more substituentsselected from R^(b) and Cy*, and any of the groups Cy or Cy* can beoptionally substituted with one or more substituents selected from R^(b)and R^(c).

Another embodiment of the invention are the compounds of formula Iwherein R³ represents monocyclic heteroaryl or phenyl, wherein all thesegroups can be optionally substituted with one or more substituentsselected from halogen, —NO₂, —OR^(c)′, C₁₋₆alkyl, haloC₁₋₆alkyl and Cy;and wherein in R³:

each R^(c′) independently represents H or R^(c);each R^(c) independently represents C₁₋₆alkyl optionally substitutedwith one or more substituents R^(d); andeach R^(d) independently represents Cy.

Another embodiment of the invention are the compounds of formula Iwherein R⁴ represents H, R^(a), halogen, —OR^(a)′, —CN, —CONR^(a′)R^(a),—NR^(a′)R^(a′) or —NR^(a′)COR^(a′).

Another embodiment of the invention are the compounds of formula Iwherein R⁴ represents H.

Another embodiment of the invention are the compounds of formula Iwherein R⁵ represents H or R⁵ represents R^(f) and is placed on the N atposition 2 of the pyrazole ring.

Another embodiment of the invention are the compounds of formula Iwherein R⁵ represents R^(f) and is placed on the N at position 2 of thepyrazole ring.

Another embodiment of the invention are the compounds of formula Iwherein R^(f) represents C₁₋₆alkyl, C₂₋₆alkenyl or Cy, wherein thegroups C₁₋₆alkyl or C₂₋₆alkenyl can be optionally substituted with oneor more substituents selected from R^(g) and Cy*, and wherein any of thegroups Cy or Cy* can be optionally substituted with one or moresubstituents selected from R^(g) and R^(a).

Another embodiment of the invention are the compounds of formula Iwherein R^(f) represents C₁₋₆alkyl, C₂₋₆alkenyl or Cy, wherein thegroups C₁₋₆alkyl or C₂₋₆alkenyl can be optionally substituted with oneor more substituents selected from R^(g) and Cy*, and wherein any of thegroups Cy or Cy* can be optionally substituted with one or moresubstituents selected from R^(g) and R^(a), wherein each R^(g)independently represents halogen, —OR^(a)′, —COR^(a)′, —CO₂R^(a)′,—CONR^(a′)R^(a)′, —NR^(a′)R^(a)′, —NR^(a′)COR^(a)′,—NR^(a′)CONR^(a′)R^(a)′, —NR^(a′)SO₂R^(a)′, —SR^(a)′, —SOR^(a′) or—SO₂R^(a′).

Another embodiment of the invention are the compounds of formula Iwherein R^(f) represents C₁₋₆alkyl, C₂₋₆alkenyl or Cy, wherein thegroups C₁₋₆alkyl or C₂₋₆alkenyl can be optionally substituted with oneor more substituents selected from R^(g) and Cy*, and wherein any of thegroups Cy or Cy* can be optionally substituted with one or moresubstituents selected from R^(g) and R^(a), wherein in R^(f):

each R^(g) independently represents —OR^(a)′, —COR^(a)′,—CONR^(a′)R^(a)′, —NR^(a′)R^(a)′, —NR^(a′)COR^(a)′,—NR^(a′)CONR^(a′)R^(a)′, —NR^(a′)SO₂R^(a)′, —SOR^(a′) or —SO₂R^(a′);each R^(a′) independently represents H or R^(a);each R^(a) independently represents Cy or C₁₋₆alkyl, wherein C₁₋₆alkylcan be optionally substituted with one or more substituents selectedfrom R^(b) and Cy*, and any of the groups Cy or Cy* can be optionallysubstituted with one or more substituents selected from R^(b) and R^(c);each R^(b) independently represents —OR^(c)′, —NR^(c′)R^(c)′, —CN,—COR^(c)′, —SR^(c′) or —SOR^(c′);each R^(c′) independently represents H or R^(c);each R^(c) independently represents C₁₋₆alkyl or Cy, wherein all thesegroups can be optionally substituted with one or more R^(d).

Another embodiment of the invention are the compounds of formula Iwherein R⁵ is placed on the N at position 2 of the pyrazole ring andrepresents R^(f), wherein R^(f) represents C₁₋₆alkyl optionallysubstituted with one or more substituents selected from —OR^(a)′,—COR^(a)′, —CONR^(a′)R^(a)′, —NR^(a′)R^(a)′, —NR^(a′)COR^(a)′,—NR^(a′)CONR^(a′)R^(a)′, —NR^(a′)SO₂R^(a′) and Cy* optionallysubstituted with one or more substituents selected from R^(a); whereinin R^(f):

each R^(a′) independently represents H or R^(a);each R^(a) independently represents Cy or C₁₋₆alkyl, wherein C₁₋₆alkylcan be optionally substituted with one or more substituents selectedfrom R^(b) and Cy*, and any of the groups Cy or Cy* can be optionallysubstituted with one or more substituents selected from R^(b) and R^(c);each R^(b) independently represents —OR^(c)′, —NR^(c′)R^(c)′, —CN,—COR^(c)′, —SR^(c′) or —SOR^(c′);each R^(c′) independently represents H or R^(c);each R^(c) independently represents C₁₋₆alkyl or Cy, wherein all thesegroups can be optionally substituted with one or more R^(d); andeach R^(d) independently represents —OR^(e′).

Another embodiment of the invention are the compounds of formula Iwherein R⁵ represents H or R⁵ represents R^(a) and is placed on the N atposition 2 of the pyrazole ring.

Another embodiment of the invention are the compounds of formula Iwherein R⁵ represents R^(a) and is placed on the N at position 2 of thepyrazole ring.

Another embodiment of the invention are the compounds of formula Iwherein R^(a) in R⁵ represents C₁₋₆alkyl, C₂₋₆alkenyl or Cy, wherein thegroups C₁₋₆alkyl or C₂₋₆alkenyl can be optionally substituted with oneor more substituents selected from R^(b) and Cy*, and wherein any of thegroups Cy or Cy* can be optionally substituted with one or moresubstituents selected from R^(b) and R^(c).

Another embodiment of the invention are the compounds of formula Iwherein R^(a) in R⁵ represents C₁₋₆alkyl, C₂₋₆alkenyl or Cy, wherein thegroups C₁₋₆alkyl or C₂₋₆alkenyl can be optionally substituted with oneor more substituents selected from R^(b) and Cy*, and wherein any of thegroups Cy or Cy* can be optionally substituted with one or moresubstituents selected from R^(b) and R^(c), wherein each R^(b) in R⁵independently represents halogen, —OR^(c)′, —COR^(c)′, —CO₂R^(c)′,—CONR^(c′)R^(c)′, —NR^(c′)R^(c)′, —NR^(c′)COR^(c)′,—NR^(c′)CONR^(c′)R^(c)′, —NR^(c′)SO₂R^(c)′, —SR^(c)′, —SOR^(c′) or—SO₂R^(c′).

Another embodiment of the invention are the compounds of formula Iwherein R^(a) in R⁵ represents C₁₋₆alkyl, C₂₋₆alkenyl or Cy, wherein thegroups C₁₋₆alkyl or C₂₋₆alkenyl can be optionally substituted with oneor more substituents selected from R^(b) and Cy*, and wherein any of thegroups Cy or Cy* can be optionally substituted with one or moresubstituents selected from R^(b) and R^(c), wherein in R⁵:

each R^(b) independently represents —OR^(c)′, —COR^(c)′,—CONR^(c′)R^(c)′, —NR^(c′)R^(c)′, —NR^(c′)COR^(c)′,—NR^(c′)CONR^(c′)R^(c)′, —NR^(c′)SO₂R^(c)′, —SOR^(c′) or —SO₂R^(c′);each R^(c′) independently represents H or R^(c);each R^(c) independently represents Cy or C₁₋₆alkyl, wherein all thesegroups can be optionally substituted with one or more substituentsselected from R^(d);each R^(d) independently represents R^(e), —OR^(e)′, —NR^(e′)R^(e)′,—CN, —COR^(e)′, —SR^(e)′, —SOR^(e′) or Cy.

Another embodiment of the invention are the compounds of formula Iwherein R⁵ is placed on the N at position 2 of the pyrazole ring andrepresents R^(a), wherein R^(a) in R⁵ represents C₁₋₆alkyl optionallysubstituted with one or more substituents selected from —OR^(c)′,—COR^(c)′, —CONR^(c′)R^(c)′, —NR^(c′)R^(c)′, —NR^(c′)COR^(c)′,—NR^(c′)CONR^(c′)R^(c)′, —NR^(c′)SO₂R^(c′) and Cy* optionallysubstituted with one or more substituents selected from R^(c); whereinin R⁵:

each R^(c′) independently represents H or R^(c);each R^(c) independently represents Cy or C₁₋₆alkyl, wherein all thesegroups can be optionally substituted with one or more substituentsselected from R^(d);each R^(d) independently represents —OR^(e)′, —NR^(e′)R^(e)′, —CN,—COR^(e)′, —SR^(e)′, —SOR^(e′) or Cy;each R^(e′) independently represents H or R^(e); andeach R^(e) independently represents C₁₋₆alkyl.

Furthermore, all possible combinations of the above-mentionedembodiments form also part of this invention.

The compounds of the present invention may contain one or more basicnitrogens and may, therefore, form salts with organic or inorganic acidsthat also form part of this invention. Examples of these salts include:salts with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, nitric acid, perchloric acid, sulfuric acid orphosphoric acid, and salts with organic acids such as methanesulfonicacid, trifluoromethanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid,acetic acid or malic acid, among others. The compounds of the presentinvention may contain one or more acidic protons and, therefore, theymay also form salts with bases, which also form part of the presentinvention. Examples of these salts include: salts with inorganic cationssuch as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc,etc; and salts formed with pharmaceutically acceptable amines such asammonia, alkylamines, hydroxylalkylamines, lysine, arginine,N-methylglucamine, procaine and the like b. There is no limitation onthe type of salt that can be used provided that these arepharmaceutically acceptable when they are used for therapeutic purposes.Salts can be prepared by treating the compound of formula I with asufficient amount of the desired acid or base to give a salt in theconventional manner. The compounds of formula I and their salts differin some physical properties but they are equivalent for the purposes ofthe present invention.

Some of the compounds of the present invention can exist in solvatedform, including hydrated forms. In general, the solvated forms withpharmaceutically acceptable solvents such as water, ethanol and the likeare equivalent to the unsolvated form for the purposes of the invention.

Some of the compounds of the present invention may exist as severaldiastereoisomers and/or several optical isomers. Diastereoisomers can beseparated by conventional techniques such as chromatography orfractional crystallization. Optical isomers can be resolved byconventional techniques of optical resolution to give optically pureisomers. This resolution can be carried out on any chiral syntheticintermediate or on products of general formula I. Optically pure isomerscan also be individually obtained using enantiospecific synthesis. Thepresent invention covers all isomers and mixtures thereof (for exampleracemic mixtures) whether obtained by synthesis and also by physicallymixing them.

Moreover, some compounds of the present invention may exhibit cis/transisomers. The present invention includes each of the geometric isomersand its mixtures.

The compounds of formula I can be obtained by following the processesdescribed below. As it is obvious to one skilled in the art the exactmethod used to prepare a given compound can vary depending on itschemical structure. Moreover, in some of the processes described belowit may be necessary or advisable to protect the reactive or labilegroups by conventional protective groups. Both the nature of theseprotective groups and the procedures followed to introduce or removethese are well known and form part of the state of the art (see forexample Greene T. W. and Wuts P. G. M, “Protective Groups in OrganicSynthesis”, John Wiley & Sons, 3^(rd) edition, 1999). As an example, asprotective groups of an amino function tert-butoxycarbonyl (Boc) orbenzyl (Bn) can be used. The carboxyl groups can be protected forexample in the form of C₁₋₆alkyl esters or arylalkyl esters, such asbenzyl, while the hydroxyl groups can be protected for example withtetrahydropyranyl (THP). Whenever a protective group is present a laterdeprotection step will be required, which can be performed understandard conditions in organic synthesis, such as those described in theabove-mentioned reference.

The compounds of formula I can be obtained in general by reaction of acompound of formula IV with an aminopyrazole of formula V and analdehyde of formula VI, as shown in the following scheme:

wherein R¹, R², R³, R⁴ and R⁵ have the same meaning as in generalformula I. This reaction is carried out preferably in the presence of aninorganic acid such as hydrochloric acid, in a suitable polar solventsuch as 2-methoxyethanol or ethanol, and heating, preferably to reflux.

The compounds of formula I wherein R⁵ represents R⁵* (i.e. compounds offormula Ia and Ib) are generally obtained by reaction of a compound offormula I wherein R⁵ represents H (i.e. a compound of formula Ic) withan alkylating agent of formula R⁵*—X (II), as shown in the followingscheme:

wherein R⁵* represents R^(a) or R^(f). R¹, R², R³, R⁴, R^(a) and R^(f)have the meaning described in general formula I and X represents aleaving group, for example an alkylsulfonate or an arylsulfonate such asmesylate or tosylate, or a halogen such as Cl, Br or I. This reaction isperformed in the presence of a base such as KOH, K₂CO₃ or NaH in asuitable solvent, such as for example acetone, toluene,dimethylformamide, 1,2-dimethoxyethane or diglyme, and heating,preferably to reflux. In the case of using apolar solvents such astoluene this reaction can be carried out in the presence of a cationsequestering agent such as crown ether 18-C-6 or a phase transfer agentsuch as a tetraalkylammonium salt.

Compounds of formula Ia and Ib wherein R^(a) represents —CH₂OH can beprepared by the reaction of a compound of formula Ic with formaldehydein a suitable polar solvent, such as water, and heating, preferably toreflux.

Compounds of formula Ia and Ib wherein R^(a) represents optionallysubstituted phenyl or optionally substituted heteroaryl can be preparedby reaction of a compound of formula Ic with a boronic acid of formulaR^(a)—B(OH)₂ (III) wherein R^(a) represents optionally substitutedphenyl or heteroaryl in the presence of a base, such as pyridine and/ortriethylamine, and in the presence of a catalyst, such as copper acetate(II), in a suitable solvent, such as an aprotic solvent such asdichloromethane.

Compounds of formula II and III are commercially available, are widelydescribed in the literature or can be prepared by methods similar tothose described, and can be conveniently protected as required.

Compounds of formula I wherein R⁵ represents H and R³ has the samemeaning as R¹ (i.e., a compound Id) can be also prepared by reaction ofa compound of formula IV with an aminopyrazole of formula Va, as shownin the following scheme:

or alternatively by, reaction of a compound of formula VII with acompound of formula Va

wherein R¹, R² and R⁴ have the meaning described in general formula I.This reaction is carried out preferably in the presence of an inorganicacid such as hydrochloric acid, in a suitable polar solvent such as2-methoxyethanol or ethanol, and heating, preferably to reflux.

Aminopyrazoles of formula V and Va and aldehydes of formula VI, arecommercially available and can be conveniently protected. Alternatively,compounds of formula Va can be conveniently prepared by reaction of acompound of formula VIII with a compound of formula IX, as shown in thefollowing scheme:

wherein R⁴ has the meaning described in general formula I. This reactionis carried out in a suitable polar solvent such as ethanol and byheating, preferably to reflux. Compounds of formula V can also beobtained by this method, starting from a compound of formula IX and acompound of formula NH₂—NHR⁵ (VIIIa).

Compounds of formula IX are commercially available and can beconveniently protected or can be conveniently prepared by reaction of acompound of formula X

with acetonitrile, in the presence of a base such as butyl lithium, in asuitable solvent such as tetrahydrofuran and at a suitable temperature,preferably −78° C.

Esters of formula X are commercially available or can be prepared bymethods widely described in the literature and can be convenientlyprotected.

Enol ethers of formula VII can be conveniently prepared by reaction of aketone of formula IV with a compound of formula R¹—COY (XI) wherein Yrepresents a halogen, preferably Cl, in the presence of a base, such asNaH, in a suitable polar solvent such as dimethylformamide.

Compounds of formula XI are commercially available or can be prepared byconventional reactions from the corresponding carboxylic acids offormula R¹—CO₂H (XII).

Compounds of formula XII are commercially available or can be preparedby methods widely described in the literature and can be convenientlyprotected.

Compounds of formula IV can be prepared by reaction of a compound offormula R¹—H (XIII) with a compound of formula XIV

wherein R¹ and R² have the meaning described in general formula I, inthe presence of a Lewis acid, such as AlCl₃, in a suitable halogenatedsolvent such as dichloromethane.

Compounds of formula XIV are commercially available or can be preparedreadily from the corresponding carboxylic acid following conventionalprocedures.

Alternatively, compounds of formula IV can be conveniently prepared byreaction of a compound of formula R²—CH₃ (XV) with a compound of formulaR¹—CN (XVI), wherein R¹ and R² have the meaning described in generalformula I, in the presence of a base such as lithium diisopropylamide,generated from butyl lithium and N,N′-diisopropylamine, in an aproticpolar solvent, such as tetrahydrofuran and cooling, preferably to −78°C.

Alternatively, compounds of formula IV can be conveniently prepared byreaction of a compound of formula R²—CH₃ (XV) with a compound of formulaR¹—CO₂R⁶ (XVII), wherein R¹ and R² have the meaning described in generalformula I and R⁶ represents C₁₋₆ alkyl, in the presence of a base suchas sodium bis(trimethylsilyl)amide or sodium hydride, in an aproticpolar solvent, such as tetrahydrofuran or dimethylformamide and at asuitable temperature, preferably room temperature.

The compounds XIII, XV, XVI and XVII are commercially available or canbe prepared by methods widely described in the literature.

Alternatively, compounds of formula IV can be conveniently prepared byreaction of a compound of formula R²—CH₃ (XV) with a compound of formulaXVIII in the same conditions as those described previously for reactionof the compound of formula XV with a compound of formula XVI.

Compounds of formula XVIII can be conveniently prepared by reaction of acompound of formula XI with N,O-dimethylhydroxylamine hydrochloride inthe presence of a base, such as triethylamine, in a suitable halogenatedsolvent such as dichloromethane and cooling, preferably to 0° C.

Alternatively, the compounds of formula XVIII can be prepared byreaction of a compound of formula XII with N,O-dimethylhydroxylaminehydrochloride in the presence of a suitable condensing agent such as forexample N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide ordicyclohexylcarbodiimide optionally in the presence of1-hydroxybenzotriazole, or in the presence of a suitable base, such aspyridine, in a suitable solvent such as dimethylformamide.

The compounds of formula I can also be obtained from a compound offormula XIX, as shown in the scheme below.

wherein R¹, R², R³, R⁴ and R⁵ have the meaning described in generalformula I. The reaction of XIX with a compound of formula VIIIa givesrise to a compound of formula I wherein R⁴=NH₂ (Ie). This reaction iscarried out in a suitable solvent such as ethanol and heating,preferably to reflux. Starting from these compounds of formula I whereinR⁴=NH₂, compounds of formula I wherein R⁴ is different from NH₂ can begenerated by interconversion reactions, explained in more detail furtheron. This method is useful to prepare compounds of formula I wherein R³represents H, optionally substituted C₁₋₆alkyl or Cy different from R¹.

Compounds of formula VIIIa are commercially available and can beconveniently protected.

Compounds of formula XIX can be conveniently prepared by reaction of acompound of formula XX

wherein R¹, R² and R³ have the meaning described in general formula I,with a chlorinating agent such as POCl₃ or PCl₃ without solvent or in asuitable solvent such as dimethylformamide and heating, preferably toreflux.

Compounds of formula XX are generally obtained by reaction of a compoundof formula XXI with 2-cyanoacetamide, as shown in the following scheme:

wherein R¹, R² and R³ have the meaning described in general formula Iand each R⁶ independently represents C₁₋₆alkyl. This reaction is carriedout in the presence of a base such as sodium methoxide, in a suitablesolvent such as dimethylformamide and heating, preferably to reflux.

Compounds of formula XXI can be conveniently prepared by reaction of acompound of formula IV with a compound of formula XXII

wherein R³ and R⁶ have the meaning previously described, in a suitablesolvent such as tetrahydrofuran.

Compounds of formula XXII are commercially available or can be preparedby methods described in the literature, for example by reacting an amideof formula XXIII

with triethyloxonium tetrafluoroborate in the presence of a base such assodium ethoxide in a suitable solvent such as ethanol or a mixture ofethanol-diethyl ether.

Alternatively, compounds of the present invention can also be obtainedby interconversion of another compound of formula I, in one or severalsteps, by using well-known reactions in organic chemistry under thereported standard experimental conditions.

Thus, R⁴ can be transformed into another R⁴, generating new compounds offormula I. For example, R⁴=H can be transformed into R⁴=Br by reactionwith an appropriate brominating agent, such as Br₂, in a suitablesolvent such as chloroform, and at an appropriate temperature comprisedbetween room temperature and the boiling point of the solvent;

or R⁴H can be converted into R⁴=Cl by reaction with an appropriatechlorinating agent such as N-chlorosuccinimide, in a suitable solventsuch as dimethylformamide at an appropriate temperature comprisedbetween room temperature and the boiling point of the solvent;

or R⁴=NH₂ can be converted into R⁴=halogen by formation of a diazoniumsalt with NaNO₂ followed by reaction with a copper halide such as CuBror CuCl, in the presence of an acid such as for example HBr or HCl;

or R⁴=NH₂ can be converted into R⁴=H by forming a diazonium salt withNaNO₂ followed by reaction with H₃PO₂, in a suitable solvent such aswater;

or R⁴=halogen can be converted into R⁴=CN by reaction with a cyanidesalt such as CuCN, in a suitable solvent such as N-methylpyrrolidone andheating, preferably to reflux.

Other conversions of R⁴, which can also be applied to R⁵ and also to thesubstituents of the R¹, R² and R³ groups to generate other compounds offormula I include, for example:

conversion of CN into CONH₂ by hydrolysis with a base such as KOH in asuitable solvent such as tert-butanol and heating, preferably to reflux;

conversion of CN into CH₂NH₂ by reaction with a reducing agent, such asLiAlH₄, in a suitable solvent such as diethyl ether;

conversion of a carboxylic acid group into an ester or an amide byreaction with an alcohol or an amine, respectively, in the presence ofan activating agent such as N,N′-dicyclohexylcarbodiimide and4-dimethylaminopyridine and in a suitable solvent such as diethyl ether;

conversion of an ester group into a carboxylic group by hydrolysis inthe presence of a base, such as KOH, in a suitable solvent such asethanol;

conversion of OH, SH or NH₂ into OR, SR and NHR or NRR, respectively, byreaction of an alkylating agent R—X wherein R represents R^(a), R^(c),R^(e) or R^(f) and X represents halogen, preferably chloro or bromo, inthe presence of a base such as triethylamine, sodium hydroxide, sodiumcarbonate, potassium carbonate or sodium hydride in a suitable solventsuch as dichloromethane, chloroform, dimethylformamide, ethanol orbutanol, at a temperature comprised between room temperature and thetemperature of the boiling point of the solvent;

alternatively, NHR can be converted into NCH₃R, wherein R representsR^(a), R^(c), R^(e) or R^(f), by reaction with formaldehyde in acidmedium, such as formic acid and heating, preferably to reflux;

conversion of an amine into an amide by reaction of a carboxylic acid inthe presence of an appropriate condensing agent such asN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide ordicyclohexylcarbodiimide optionally in the presence of1-hydroxybenzotriazole, or in the presence of an appropriate base suchas pyridine, in a suitable solvent, such as dimethylformamide; oralternatively, an amine can be converted into an amide by reaction withan acyl chloride in pyridine or in the presence of a base such astriethylamine in a suitable solvent such as dichloromethane, andcooling, preferably to 0° C.;

conversion of an amine into a urea or a carbamate by a two step sequencethat involves reacting the amine with an activating agent such astriphosgene, in the presence of a base such as diisopropylethylamine,triethylamine or N-methylmorpholine, in a suitable solvent such asacetonitrile or a halogenated hydrocarbon such as chloroform ordichloromethane, and then reacting the resulting compound with thesecond amine in the case of a urea or with an alcohol in the case of acarbamate, in a suitable solvent, such as the solvent used in the firststep; or alternatively an amine can be converted into a urea orcarbamate by reaction with an isocyanate or a chloroformate,respectively, in a suitable solvent, such as dimethylformamide, at asuitable temperature, preferably room temperature;

conversion of an amine into a sulfonamide by reaction with a sulfonylhalide, such as sulfonyl chloride, optionally in the presence of a basesuch as 4-dimethylaminopyridine, in a suitable solvent such as dioxane,chloroform, dichloromethane or pyridine;

conversion of a hydroxyl group into an ester group by reaction with acarboxylic acid in the standard conditions mentioned previously;

conversion of a sulfanyl group into a sulfinyl or sulfonyl group byreaction with 1 or 2 equivalents, respectively, of an appropriateoxidizing agent such as m-chloroperbenzoic acid in a suitable solventsuch as for example dichloromethane;

conversion of a primary or secondary hydroxyl group into a leavinggroup, for example an alkylsulfonate or arylsulfonate such as mesylateor tosylate or a halogen such as Cl, Br or I, by reaction with asulfonyl halide such as methanesulfonyl chloride, in the presence of abase, such as pyridine or triethylamine, in a suitable solvent such asdichloromethane or chloroform, or with a halogenating agent, such asSOCl₂, in a suitable solvent such as tetrahydrofuran;

the substitution of said leaving group by reaction with an alcohol,amine or thiol, optionally in the presence of a base, such as K₂CO₃, andin a suitable solvent such as dimethylformamide, 1,2-dimethoxyethane oracetonitrile;

the elimination of a leaving group bonded to an alkyl group to give analkenyl group by reaction with a base, such as KOH, in a suitablesolvent, such as toluene and heating, preferably to reflux;

conversion of a primary amide into a secondary amide by reaction with analkylating agent in the presence of a strong base, such as sodiumhydride, in a suitable solvent and at a temperature comprised betweenroom temperature and the boiling point of the solvent;

conversion of CHO into an amine by reaction with an amine in thepresence of a reducing agent such as sodium triacetoxyborohydride, in asuitable solvent such as for example 1,2-dichloroethane;

conversion of an acetal group into an aldehyde by reaction in acidmedium, for example in HCl, at an appropriate temperature, preferably toreflux;

conversion of an ester group into an alcohol group by reaction with areducing agent, such as LiAlH₄, in a suitable solvent, such astetrahydrofuran;

conversion of a sulfonyl group bonded to an aromatic ring into an aminoderivative by reaction with the corresponding amine, in a suitablesolvent such as tetrahydrofuran or using the amine as a solvent,heating, preferably to a temperature comprised between room temperatureand 100° C. and preferably carrying out the reaction in a closed vesselunder atmospheric pressure;

conversion of a sulfonyl group bonded to an aromatic ring bydisplacement with an alkoxide to give the corresponding alkoxyderivative, in a suitable solvent such as tetrahydrofuran or using thecorresponding alcohol as a solvent, heating, preferably to a temperaturecomprised between room temperature and 100° C. and preferably carryingout the reaction in a closed vessel under atmospheric pressure;

conversion of a vinylic or aromatic halogen into NHR, wherein Rrepresents R^(a), R^(c), R^(e) or R^(f), by reacting with an amine offormula H₂NR and preferably heating;

alternatively, a vinylic or aromatic halogen can be converted into NHRby reaction with an amine of formula H₂NR in the presence of a base,such as Cs₂CO₃ or sodium tert-butoxide, in the presence of a palladiumcatalyst, such as palladium acetate (II), and a phosphine such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in a solvent, such astoluene, and preferably heating;

conversion of a vinylic or aromatic halogen into a phenyl or heteroarylgroup by treatment with a phenyl- or a heteroarylboronic acid in thepresence of a catalyst, such as a palladium catalyst, such as palladiumacetate (II) or tetraquis(triphenylphosphine) palladium (0) and of abase such as Na₂CO₃, K₂CO₃ or CsF, in a suitable polar solvent, such as1,2-dimethoxyethane or toluene-water mixtures, and preferably heating;

conversion of an aromatic halogen into H by halogenolysis, with areducing agent such as Zn, in a suitable solvent, such as acetic acidand heating, preferably to reflux; and

oxidation of the N at position 7 of the pyrazolo[3,4-b]pyridine ring togive the corresponding N-oxide by reaction with an oxidizing agent, suchas m-chloroperbenzoic acid, in a suitable solvent, such as for exampledichloromethane.

Likewise, any of the aromatic rings of the compounds of the presentinvention can undergo electrophilic aromatic substitution reactions,widely described in the literature.

Many of these interconversion reactions are explained in greater detailin the examples.

As it will be obvious to those skilled in the art, these interconversionreactions can also be carried out on synthesis intermediates ofcompounds of formula I.

The present invention also includes the salts of the compounds offormula I. These salts can be prepared by conventional methods bytreating a compound of formula I with an appropriate amount of an acidsuch as hydrochloric acid, sulfuric acid, nitric acid, oxalic acid ormethanesulfonic acid. In the case of compounds of formula I that containan acidic proton, salts can also be obtained. by treatment with a basesuch as sodium hydroxide, potassium hydroxide, calcium hydroxide orcalcium carbonate. Salts of the compounds of formula I can be convertedin turn into other salts of compounds of formula I by ion exchange usinga ionic exchange resin.

As mentioned previously, the compounds of the present invention act asp38 kinase inhibitors, inducing reduction of proinflammatory cytokines.Therefore, these compounds are expected to be useful to treat or preventdiseases in which kinase p38 plays a role. This includes diseases causedby overproduction of cytokines such as TNF-α, IL-1, IL-6 or IL-8. Thesediseases include, but are not limited to, immune, autoimmune andinflammatory diseases, cardiovascular diseases, infectious diseases,bone resorption disorders, neurodegenerative diseases, proliferativediseases and processes associated with cyclooxygenase-2 induction.

As an example, immune, autoimmune and inflammatory diseases that can betreated or prevented with the compounds of the present invention includerheumatic diseases (e.g. rheumatoid arthritis, psoriatic arthritis,infectious arthritis, progressive chronic arthritis, deformingarthritis, osteoarthritis, traumatic arthritis, gouty arthritis,Reiter's syndrome, polychondritis, acute synovitis and spondylitis),glomerulonephritis (with or without nephrotic syndrome), autoimmunehematologic disorders (e.g. hemolytic anemia, aplasic anemia, idiopathicthrombocytopenia and neutropenia), autoimmune gastritis and autoimmuneinflammatory bowel diseases (e.g. ulcerative colitis and Crohn'sdisease), host versus graft disease, allograft rejection, chronicthyroiditis, Graves' disease, schleroderma, diabetes (type I and typeII), active hepatitis (acute and chronic), primary binary cirrhosis,myasthenia gravis, multiple sclerosis, systemic lupus erythematosus,psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns,chronic renal insufficiency, Stevens-Johnson syndrome, idiopathic sprue,sarcoidosis, Guillain-Barré syndrome, uveitis, conjunctivitis,keratoconjunctivitis, otitis media, periodontal disease, pulmonaryinterstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis,pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema,pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease(e.g. chronic obstructive pulmonary disease) and other inflammatory orobstructive diseases of the airways.

Cardiovascular diseases that can be treated or prevented include, amongothers, myocardial infarction, cardiac hypertrophy, cardiacinsufficiency, ischaemia-reperfusion disorders, thrombosis,thrombin-induced platelet aggregation, acute coronary syndromes,atherosclerosis and cerebrovascular accidents.

Infectious diseases that can be treated or prevented include, amongothers, sepsis, septic shock, endotoxic shock, sepsis by Gram-negativebacteria, shigellosis, meningitis, cerebral malaria, pneumonia,tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitisB and hepatitis C), HIV infection, retinits caused by cytomegalovirus,influenza, herpes, treatment of infections associated with severe burns,myalgias caused by infections, cachexia secondary to infections, andveterinary viral infections such as lentivirus, caprine arthritic virus,visna-maedi virus, feline immunodeficiency virus, bovineimmunodeficiency virus or canine immunodeficiency virus.

Bone resorption disorders that can be treated or prevented includeosteoporosis, osteoarthritis, traumatic arthritis, gouty arthritis andbone disorders related with multiple myeloma, among others.

Neurodegenerative diseases that can be treated or prevented includeAlzheimer's disease, Parkinson's disease, cerebral ischaemia andtraumatic neurodegenerative disease, among others.

Proliferative diseases that can be treated or prevented includeendometriosis, solid tumors, acute and chronic myeloid leukemia, Kaposisarcoma, multiple myeloma, metastatic melanoma and angiogenic disorderssuch as ocular neovascularisation and infantile haemangioma.

p38 kinase inhibitors also inhibit the expression of proinflammatoryproteins such as cyclooxygenase-2 (COX-2), the enzyme responsible forprostaglandin production. Therefore, the compounds of the presentinvention can also be used to treat or prevent diseases mediated byCOX-2 and especially to treat processes with inflammation, fever andneuromuscular pain such as cephalea, pain caused by cancer, tooth painand arthritic pain.

According to the activity of the products herein described, the presentinvention also relates to compositions which contain a compound of thepresent invention, together with an excipient or other auxiliary agentsif necessary. The compounds of the present invention can be administeredin the form of any pharmaceutical formulation, the nature of which, asit is well known, will depend upon the nature of the active compound andits route of administration. Any route of administration may be used,for example oral, parenteral, nasal, ocular, rectal and topicaladministration.

According to the present invention, solid compositions for oraladministration include tablets, granulates and capsules. In any case themanufacturing method is based on a simple mixture, dry granulation orwet granulation of the active compound with excipients. These excipientscan be, for example, diluents such as lactose, microcrystallinecellulose, mannitol or calcium hydrogenphosphate; binding agents such asfor example starch, gelatin or povidone; disintegrants such as sodiumcarboxymethyl starch or sodium croscarmellose; and lubricating agentssuch as for example magnesium stearate, stearic acid or talc. Tabletscan be additionally coated with suitable excipients by using knowntechniques with the purpose of delaying their disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period, or simply to improve their organolepticproperties or their stability. The active compound can also beincorporated by coating onto inert pellets using natural or syntheticfilm-coating agents. Soft gelatin capsules are also possible, in whichthe active compound is mixed with water or an oily medium, for examplecoconut oil, mineral oil or olive oil.

Powders and granulates for the preparation of oral suspensions by theaddition of water can be obtained by mixing the active compound withdispersing or wetting agents, suspending agents and preservatives. Otherexcipients can also be added, for example sweetening, flavouring andcolouring agents.

Liquid forms for oral administration include emulsions, solutions,suspensions, syrups and elixirs containing commonly-used inert diluents,such as purified water, ethanol, sorbitol, glycerol, polyethyleneglycols (macrogolsy and propylene glycol. Said compositions can alsocontain coadjuvants such as wetting, suspending, sweetening, flavouringagents, preservatives and buffers.

Injectable preparations, according to the present invention, forparenteral administration, comprise sterile solutions, suspensions oremulsions, in an aqueous or non-aqueous solvent such as propyleneglycol, polyethylene glycol or vegetable oils. These compositions canalso contain coadjuvants, such as wetting, emulsifying, dispersingagents and preservatives. They may be sterilized by any known method orprepared as sterile solid compositions which will be dissolved in wateror any other sterile injectable medium immediately before use. It isalso possible to start from sterile materials and keep them under theseconditions throughout all the manufacturing process.

For the rectal administration, the active compound can be preferablyformulated as a suppository on an oily base, such as for examplevegetable oils or solid semisynthetic glycerides, or on a hydrophilicbase such as polyethylene glycols (macrogol).

The compound can also be formulated for its topical application for thetreatment of pathologies occurring in zones or organs accessible throughthis route, such as eyes, skin and the intestinal tract. Formulationsinclude creams, lotions, gels, powders, solutions and patches whereinthe compound is dispersed or dissolved in suitable excipients.

The compounds of the present invention can also be formulated as a solidform, dissolved or dispersed in a suitable vehicle, for inhalation insingle or multidose container. Preparations to be administered as anaerosol (dispersion of solid or liquid particles in a gas) use suitabledevices such as nebulisers, pressured metered-dose inhalers ordry-powder inhalers. Depending on this, the compound will be formulatedwith excipients such as propellants responsible for developing theproper pressure within the container to force the content out throughthe opening of the valve, solvents, emulsifying agents,viscosity-increasing agents, preservatives, stabilizing agents andlubricants to avoid the blockade of the valve.

The dosage and frequency of doses will depend upon the nature andseverity of the disease to be treated, the age, the general conditionand body weight of the patient, as well as the particular compoundadministered and the route of administration, among other factors. Arepresentative example of a suitable dosage range is from about 0.01mg/Kg to about 100 mg/Kg per day, which can be administered as a singleor divided doses. However, the dosage administered is generally left tothe discretion of the physician.

The activity of the compounds of this invention can be assessed usingthe following tests:

Test 1: Inhibition of TNF-α Release Induced by LPS in Human HistiocyticLymphoma Cells, U-937

Maintenance and differentiation of U-937 cells: U-937 cells (ATCC N^(o)CRL-159.2) are cultivated in RPMI 1640 medium supplemented with 10%inactivated fetal bovine serum (Gibco). A total of 0.5×10⁶ cells areincubated in the presence of 20 ng/mL of PMA (phorbol 12-myristate13-acetate) for 24 h to achieve complete monocytic differentiation. Allthe incubations are carried out at 37° C. in an atmosphere with 5% CO₂.The cells are centrifuged (200×g for 5 min) and resuspended in RPMI 1640medium supplemented with 2% inactivated fetal bovine serum at a densityof 2×10⁶ cells/mL.

Inhibition of TNF-α release: 100 μL of cells U-937 (2×10⁶ cells/mL) areincubated with 100 μL of the test product (final concentration, 0.001-10μM) for 30 min in 96-well plates. The mother solutions of the products(10 mM in DMSO) are diluted in culture medium to reach a final DMSOconcentration equal to or less than 0.1%. A total of 20 μL of LPS (E.coli 055B5, Sigma) are added to a final concentration of 100 ng/mL andafter incubation for 4 hours the amount of TNF-α released in thesupernatant is quantified using a commercial ELISA kit (BiosourceInternational).

Test 2: Inhibition of TNF-α Release Induced by LPS in Human PeripheralBlood Mononuclear Cells

To obtain the mononuclear cells: heparinized venous blood, obtained fromhealthy volunteers, is diluted with an equal volume of saline phosphatebuffer without calcium or magnesium. Aliquots of 30 mL of the mixtureare transferred to 50 mL centrifuge tubes containing 15 mL ofFicoll-Hypaque (1.077 g/mL). The tubes are centrifuged at 1200×g for 20min at room temperature without braking. Approximately two-thirds of theband of platelets lying above the mononuclear cells is removed with apipette. The mononuclear cells are carefully transferred to a 50 mLtube, washed twice with saline phosphate buffer, centrifuged at 300×gfor 10 min at room temperature and resuspended in RPMI supplemented with1% inactivated fetal bovine serum at a cell density of 2×10⁶ cells/mL.

Inhibition of TNF-α release: 100 μL of mononuclear cells (2×10⁶cells/mL) are incubated on 96-well plates with 50 μL of the test product(final concentration, 0.001-10 μM) and 50 μL LPS (E. coli 055B5, Sigma)at a final concentration of 400 ng/mL for 19 h at 37° C. in anatmosphere with CO₂ at 5%. The amount of TNF-α released in thesupernatant is quantified using a commercial ELISA kit (BiosourceInternational).

Test 3: Inhibition of p38-α Kinase:

In a final volume of 25 μL, a total of 5 μL of the test product (finalconcentration, 0.001-10 μM), 5-10 mU of p38-α with 0.33 mg/mL of myelinbasic protein, Mg²⁺ acetate (10 mM) and [γ³³P-ATP] (100 μM, specificactivity 500 cpm/pmol) in buffer Tris 25 mM pH7.5, EGTA 0.02 mM isincubated. The reaction is started by adding Mg²⁺[γ³³P-ATP]. Afterincubation for 40 min at room temperature, the reaction is quenched byadding 5 μL of 3% phosphoric acid solution. The reaction mixture (10 μL)is passed through a filter (P30) and washed three times for 5 min with a75 mM phosphoric acid solution and once with methanol before drying itand counting it, by liquid scintillation.

The following table shows the results obtained with representativecompounds of the invention in test 2:

% Inhibition Example at 0.1 μM 1 57.5 4 68.4 6 81.4 8 66.3 18 82.6 2256.5 30 83.6 36 92.0 39 51.1 41 90.6 43 61.2 56 58.7 59 60.0 63 53.2 6850.0 72 52.7 78 73.3 80 69.3 82 59.9 90 86.3 102 67.9 106 69.3 121 52.1128 82.0 136 67.0 137 61.4 183 66.7 184 71.2 188 73.2 196 70.2 208 67.7209 84.2 210 57.3 211 70.6 212 67.5 213 68.1 214 71.1 217 53.8 232 67.9237 53.4 240 58.4 248 53.2 250 67.0 268 69.1 272 65.6 279 100.0 282 65.2283 52.4 287 71.2 289 51.3 290 65.8

The following examples illustrate, but do not limit, the scope of theinvention.

The following abbreviations have been used in the examples:

-   AcOH: acetic acid-   EtOAc: ethyl acetate-   NH₄OAc: ammonium acetate-   BuLi: butyl lithium-   ^(t)BuOH: tert-butanol-   conc.: concentrated-   DMAP: 4-(N,N-dimethylamino)pyridine-   DMF: dimethylformamide-   EtOH: ethanol-   MeOH: methanol-   THF: tetrahydrofuran-   t_(R): retention time-   LC-MS: liquid chromatography-mass spectrometry

LC-MS spectra have been performed using the following chromatographicmethods:

Method 1: Column Tracer Excel 120, ODSB 5 μm (10 mm×0.21 mm),temperature: 30° C., flow: 0.35 mL/min, eluent: A=acetonitrile, B=0.1%HCOOH, gradient: 0 min 10% A-10 min 90% A.

Method 2: Column X-Terra MS C18 5 μm (150 mm×2.1 mm), temperature: 30°C., flow: 0.40 mL/min, eluent: A=acetonitrile, B=10 mM NH₄OAc (pH=6.80),gradient: 0 min 25% A-6 min 80% A-7.5 min 25% A.

REFERENCE EXAMPLE 1 1-(4-Fluorophenyl)-2-(4-pyridyl)ethanone a)4-Fluoro-N-methoxy-N-methylbenzamide

In a volumetric flask N,O-dimethylhydroxylamine hydrochloride (25.54 g,261.8 mmol) and CH₂Cl₂ (443 mL) were introduced under argon atmosphereat 0° C. 4-Fluorobenzoyl chloride (34.59 g, 218.2 mmol) was addedfollowed by the slow addition of triethylamine (48.13 g, 475.6 mmol).The reaction was stirred for 30 min at 5° C. and allowed to reach roomtemperature. It was washed with 5% aqueous citric acid (180 mL) and with5% aqueous NaHCO₃ (180 mL). The aqueous phase was extracted with CH₂Cl₂.The organic phase was dried over Na₂SO₄ and concentrated to dryness, toafford 20.23 g of the desired compound (yield: 88%).

b) Title Compound

To a solution of diisopropylamine (23.4 mL, 165.7 mmol) in THF (250 mL),cooled to −78° C., BuLi (103.5 mL of a 1.6 M solution in hexane, 165.7mmol) was added dropwise under argon atmosphere. After ˜5 minutes, asolution of 4-methylpyridine (10.28 g, 110.4 mmol) in THF (85 mL) wasadded over 20 min. The mixture was stirred at 0° C. for 15 min and asolution of 4-fluoro-N-methoxy-N-methylbenzamide (obtained in section a)in THF (85 mL) was added over 30 min period. The reaction was allowed toreach room temperature. Water (100 mL) and EtOAc (100 mL) were added andthe mixture was stirred for 30 min. The organic phase was separated,dried over Na₂SO₄ and concentrated to dryness, to afford 24.32 g of thedesired compound (yield: 100%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.29 (s, 2H), 7.14-7.23 (complexsignal, 4H), 8.05 (m, 2H), 8.59 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

REFERENCE EXAMPLE 2 2-(4-Pyridyl)-1-[3-(trifluoromethyl)phenyl]ethanonea) N-Methoxy-N-methyl-3-(trifluoromethyl)benzamide

Following a similar procedure to that described in reference example 1section a, but using 3-(trifluoromethyl)benzoyl chloride instead of4-fluorobenzoyl chloride, the desired product was obtained (yield: 86%).

b) Title Compound

Following a similar procedure to that described in reference example 1section b, but using N-methoxy-N-methyl-3-(trifluoromethyl)benzamide(obtained in section a of this example) instead of4-fluoro-N-methoxy-N-methylbenzamide, the title compound was obtained(yield: 22%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.31 (s, 2H), 7.20 (d, J=5.8 Hz, 2H),7.63 (t, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.16 (d, J=7.9 Hz, 1H),8.24 (s, 1H), 8.56 (d, J=5.8 Hz, 2H).

REFERENCE EXAMPLE 3 1-Phenyl-2-(4-pyridyl)ethanone

A solution of diisopropylamine (22 mL, 15.03 mmol) in THF (200 mL) underargon atmosphere was cooled to −78° C. BuLi (96 mL of a 1.6 M solutionin hexane, 153.0 mmol) was added dropwise. After 1 h, a solution of4-methylpyridine (15.00 g, 161.1 mmol) in THF (75 mL) was added andallowed to warm to 0° C. At this temperature it was stirred for 30minutes. It was cooled to −78° C. and benzonitrile (18.27 g, 177.2 mmol)in THF (75 mL) was added and stirred at −78° C. for 2 h. It was stirredat room temperature overnight. Water (225 mL) was added, it was cooledwith a water-ice bath and adjusted to pH 1 with 48% HBr. The organicphase was separated. The aqueous phase was heated to reflux for 2 h,allowed to cool and extracted with diethyl ether. The aqueous phase wastaken to neutral pH with 1 N NaOH and extracted with EtOAc. The organicphase was dried over Na₂SO₄ and concentrated to dryness, to afford 28.53g of title compound (yield: 90%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.29 (s, 2H), 7.20 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 7.49 (m, 2H), 7.58 (m, 1H), 8.00 (d, J=8.2 Hz, 2H),8.56 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

REFERENCE EXAMPLE 4 1-(4-Fluorophenyl)-2-(4-pyridyl)vinyl4-fluorobenzoate

To a suspension of NaH (0.81 g, 18.6 mmol) in DMF (30 mL) under argonatmosphere and cooled to 0° C., a solution of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (2.00 g, 9.3 mmol, obtained inreference example 1) in DMF (15 mL) was added and stirred to roomtemperature for 30 minutes. It was then cooled to 0° C. and a solutionof 4-fluorobenzoyl chloride (2.95 g, 1.9 mmol) in DMF (10 mL) was added.It was stirred at room temperature overnight. Water was added and thesolvent was evaporated off. The residue was dissolved in a mixture ofCHCl₃ and water and the phases were separated. The aqueous phase wasextracted with CHCl₃ (×3). The organic phase was washed with water (×2),dried over Na₂SO₄ and concentrated to dryness. The crude productobtained was purified by chromatography on silica gel using hexane-EtOAcmixtures of increasing polarity as eluent, to afford 0.98 g of thedesired compound as a yellow solid (yield: 31%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 6.68 (s, 1H), 7.11 (t, J=8.6 Hz, 2H),7.29 (t, J=8.6 Hz, 2H), 7.39 (d, J=6.0 Hz, 2H), 7.60 (dd, J_(o)=5.2 Hz,J_(m)=8.8 Hz, 2H), 8.27 (dd, J_(o)=5.4 Hz, J_(m)=8.8 Hz, 2H), 8.58 (d,J=6.0 Hz, 2H)

REFERENCE EXAMPLE 5 1-Phenyl-2-(4-pyridyl)vinyl benzoate

Following a similar procedure to that described in reference example 4,but using 1-phenyl-2-(4-pyridyl)ethanone (obtained in reference example3) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and benzoylchloride instead of 4-fluorobenzoyl chloride, the title compound wasobtained (yield: 62%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 6.72 (s, 1H), 7.38-7.42 (complexsignal, 5H), 7.60-7.63 (complex signal, 4H), 7.71 (t, J=7.4, 1H), 8.23(d, J=7.1 Hz, 2H), 8.51 (dd, J_(o)=1.5 Hz, J_(m)=4.6 Hz, 2H).

REFERENCE EXAMPLE 62-[2-(Methylsulfanyl)pyrimidin-4-yl]-1-[3-(trifluoromethyl)phenyl]ethanonea) 4-Methyl-2-(methylsulfanyl)pyrimidine

To a solution of NaOH (7.46 g, 186.4 mmol) in water (120 mL),4-methylpyrimidine-2-thiol hydrochloride (13.78 g, 84.7 mmol) was addedand subsequently iodomethane (13.23 g, 93.2 mmol) was added dropwiseunder argon atmosphere. It was stirred at room temperature for 2 h. Itwas extracted with CH₂Cl₂ (×2). The organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 10.26 g of the desired compound (yield:86%).

b) Title Compound

Following a similar procedure to that described in reference example 1section b, but using N-methoxy-N-methyl-3-(trifluoromethyl)benzamide(obtained in section a of the reference example 2) instead of4-fluoro-N-methoxy-N-methylbenzamide and4-methyl-2-(methylsulfanyl)pyrimidine (obtained in section a of thisexample) instead of 4-methylpyridine, the title compound as a crudeproduct was obtained that was directly used in the following reactions(yield: quantitative).

REFERENCE EXAMPLE 73-(Dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one

To a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (0.30 g, 1.4mmol, obtained in reference example 1) in anhydrous THF (5 mL), dimethyldimethylformamide acetal (0.27 g, 3.2 mmol) was added under argonatmosphere. This was stirred overnight at room temperature. The solventwas evaporated to afford 0.39 g of the title compound (yield:quantitative).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.79 (s, 6H), 6.97 (t, J=8.7 Hz, 2H),7.05 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.38 (s, 1H), 7.45 (m, 2H),8.48 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

REFERENCE EXAMPLE 83-(Dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one

Following a similar procedure to that described in reference example 7,but using2-[2-(methylsulfanyl)pyrimidin-4-yl]-1-[3-(trifluoromethyl)phenyl]ethanone(obtained in reference example 6) instead of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone, the desired compound wasobtained in the form of a crude product that was directly used in thefollowing reactions.

REFERENCE EXAMPLE 9 1-(6-Chloropyridin-3-yl)-2-(4-pyridyl)ethanone a)6-Chloronicotinoyl chloride hydrochloride

A solution of 6-chloronicotinic acid (10.00 g, 63.5 mmol) in SOCl₂ (37mL) was heated to reflux for 2 h. The SOCl₂ was evaporated to dryness,to afford 12.56 g of the desired product (yield: 93%).

b) 6-Chloro-N-methoxy-N-methylnicotinamide

Following a similar procedure to that described in reference example 1section a, but using 6-chloronicotinoyl chloride hydrochloride (obtainedin section a of this example) instead of 4-fluorobenzoyl chloride, thedesired compound was obtained (yield: 71%).

c) Title Compound

Following a similar procedure to that described in reference example 1section b, but using 6-chloro-N-methoxy-N-methylnicotinamide (obtainedin section b of this example) instead of4-fluoro-N-methoxy-N-methylbenzamide, the title compound was obtained(yield: quantitative).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.27 (s, 2H), 7.18 (dd; J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 7.45 (dd, J_(o)=0.6 Hz, J_(m)=8.4 Hz, 1H), 8.20 (dd,J_(o)=2.5 Hz, J_(m)=8.3 Hz, 2H s, 1H), 8.56 (18 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 8.98 (d, J=2.4 Hz, 1H).

REFERENCE EXAMPLE 102-(4-Fluorophenyl)-6-hydroxy-3,4′-bipyridine-5-carbonitrile

To a solution of3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one (12.77g, 47.2 mmol, obtained in reference example 7) in DMF (175 mL),2-cyanoacetamide (4.41 g, 52.0 mmol) was added under argon atmosphere.Then, sodium methoxide (5.35 g, 99.2 mmol) was added and heated toreflux for 1 hour. The mixture was allowed to cool, concentrated anddiluted with water. The pH was adjusted to 4 with 1 N HCl. A precipitatewas obtained that was filtered and dried to give 6.57 g of the desiredcompound as a solid (yield: 48%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.20 (s, OH+NH+CD₃OD), 6.96 (dd,J_(o)=1.6 Hz, J_(m)=4.5 Hz, 2H), 7.05 (t, J=8.7 Hz, 2H), 7.23 (m, 2H),7.96 (s, 1H), 8.39 (dd, J_(o)=1.4 Hz, J_(m)=4.6 Hz, 2H).

REFERENCE EXAMPLE 112-Hydroxy-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]pyridine-3-carbonitrile

Following a similar procedure to that described in reference example 10,but using3-(dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one(obtained in reference example 8) instead of3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one, thetitle compound was obtained (yield: 20%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 3.28 (s, 3H), 3.84 (s, OH+CD₃OD),6.38 (d, J=5.4 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H),7.61 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 8.18 (d, J=5.1 Hz, 1H), 8.35 (s,1H).

REFERENCE EXAMPLE 126-Chloro-2-(4-fluorophenyl)-3,4′-bipyridine-5-carbonitrile

A mixture of 2-(4-fluorophenyl)-6-hydroxy-3,4′-bipyridine-5-carbonitrile(6.57 g, 22.5 mmol, obtained in reference example 10), POCl₃ (26.3 mL,287.5 mmol) and DMF (0.37 mL) was heated to reflux under argonatmosphere for 2 h. It was cooled with an ice bath and basified byadding 30% aqueous NH₃. The precipitate obtained was filtered and washedwith water. The product was purified by chromatography on silica gelusing hexane-EtOAc mixtures of increasing polarity as eluent, to afford3.86 g of the desired product as a yellow solid (yield: 55%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 7.00 (t, J=8.6 Hz, 2H), 7.11 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 7.37 (m, 2H), 7.98 (s, 1H), 8.62 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

REFERENCE EXAMPLE 13 1-(6-Methylpyridin-3-yl)-2-(4-pyridyl)ethanone a)N-Methoxy-6,N-dimethylnicotinamide

To a solution of 6-methylnicotinic acid (5.00 g, 36.5 mmol) in DMF (150mL), 1-hydroxybenzotriazole (4.92 g, 36.5 mmol),N-ethyl-N-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.38 g,45.7 mmol) and 4-methylmorpholine (16.0 mL, 145.8 mmol) were added underargon atmosphere. The mixture was stirred at room temperature for 30minutes after which N,O-dimethylhydroxylamine hydrochloride was added(3.55 g, 36.5 mmol). The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated off. The residue wasdissolved in a mixture of CHCl₃ and 0.2 N NaHCO₃. The phases wereseparated and the aqueous phase was extracted with CHCl₃. The organicphase was dried over Na₂SO₄ and concentrated to dryness. The product waspurified by chromatography on silica gel using hexane-EtOAc mixtures ofincreasing polarity as eluent, to afford 1.11 g of the desired product(yield: 29%).

b) Title Compound

Following a similar procedure to that described in reference example 1section b, but using N-methoxy-6,N-dimethylnicotinamide (obtained insection a of this example) instead of4-fluoro-N-methoxy-N-methylbenzamide, the title compound was obtained(yield: 87%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.64 (s, 3H), 4.28 (s, 2H), 7.20 (dd,J_(o)=1.4 Hz, J_(m)=4.6 Hz, 2H), 7.28 (d, J=8.1 Hz, 1H), 8.15 (dd,J_(o)=2.4 Hz, J_(m)=8.1 Hz, 1H), 8.57 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz,2H), 9.10 (d, J=2.4 Hz, 1H).

REFERENCE EXAMPLE 142-Chloro-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]pyridine-3-carbonitrile

Following a similar procedure to that described in reference example 12but using2-hydroxy-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]pyridine-3-carbonitrile(obtained in reference example 11) instead of2-(4-fluorophenyl)-6-hydroxy-3,4′-bipyridine-5-carbonitrile, the titlecompound was obtained (yield: 44%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.48 (s, 3H), 6.62 (d, J=5.1 Hz, 1H),7.51 (m, 2H), 7.71 (d, J=7.2 Hz, 1H), 7.82 (s, 1H), 8.39 (d, J=5.1 Hz,1H), 8.42 (s, 1H), 8.42 (s, 1H).

REFERENCE EXAMPLE 15 3-Amino-5-(1-benzylpiperidin-4-yl)-2H-pyrazole a)Methyl 1-benzylpiperidine-4-carboxylate

To a solution of methyl piperidine-4-carboxylate (10.00 g, 6.4 mmol) andtriethylamine (10.32 g, 10.2 mmol) in CHCl₃ (100 mL), benzyl bromide(14.69 g, 8.6 mmol) was added under argon atmosphere while cooling witha water and ice bath. The mixture was stirred at room temperatureovernight. CHCl₃ and water were added and the two phases were separated.The aqueous phase was extracted with CHCl₃. The organic phase was driedover Na₂SO₄ and concentrated to dryness, to afford 13.80 g of thedesired compound as an orange solid (yield: 88%).

b) 3-(1-Benzylpiperidin-4-yl)-3-oxopropiononitrile

To a solution of BuLi (12.4 mL of a 1.6 M solution in hexane, 19.8 mmol)in THF (25 mL) cooled to −78° C., acetonitrile (1 mL) was added dropwiseunder argon atmosphere. After stirring the resulting suspension for 5min at −78° C., a solution of methyl 1-benzylpiperidine-4-carboxylate(2.0 g, 8.1 mmol, obtained in the previous section) in THF (5 mL) wasadded dropwise and stirred for 30 min at −78° C. It was allowed to reachroom temperature and stirred at this temperature overnight. 1 N HCl wasadded to adjust the pH to 7 and the aqueous phase was extracted withCHCl₃. The organic phase was dried over Na₂SO₄ and concentrated todryness, to afford 1.92 g of the desired compound in a solid orange form(yield: 98%).

c) Title Compound

To a solution of 3-(1-benzylpiperidin-4-yl)-3-oxopropiononitrile (1.85g, 7.6 mmol, obtained in the previous section) in EtOH (77 mL),hydrazine monohydrate (0.74 mL, 15.3 mmol) was added under argonatmosphere. The mixture was heated to reflux overnight. The solvent wasevaporated and the residue was dissolved in a mixture of water-CHCl₃.The aqueous phase was extracted with CHCl₃. The organic phase was driedover Na₂SO₄ and concentrated to dryness. The crude product obtained waspurified by chromatography on silica gel using hexane-EtOAc mixtures ofincreasing polarity as eluent, to afford 0.46 g of the desired compound(yield: 23%)

¹H NMR (300 MHz, CD₃OD) δ (TMS): 1.72 (m, 2H), 1.90 (m, 2H), 2.15 (m,2H), 2.56 (m, 1H), 2.97 (m, 2H), 3.57 (s, 2H), 4.89 (broad s,NH+NH₂+H₂O), 5.43 (s, 1H), 7.27-7.34 (complex signal, 5H).

REFERENCE EXAMPLE 163-(Dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)but-2-en-1-one

Following a similar procedure to that described in reference example 7,but using dimethylacetamide dimethyl acetal instead of dimethylformamidedimethyl acetal, the desired compound was obtained in the form of acrude product that was directly used in the following reactions.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.15 (5, 3H), 3.00 (s, 6H), 6.80 (m,4H), 7.45 (m, 2H), 8.30 (d, J=8.0 Hz, 2H).

REFERENCE EXAMPLE 172-(4-Fluorophenyl)-6-hydroxy-4-methyl-3,4′-bipyridine-5-carbonitrile

Following a similar procedure to that described in reference example 10,but using3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)but-2-en-1-one(obtained in reference example 16) instead of3-dimethylamino-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one, thetitle compound was obtained (yield: 21%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.55 (broad s, OH+H₂O), 2.30 (s, 3H),6.97 (m, 4H), 7.25 (m, 2H), 8.52 (m, 2H).

REFERENCE EXAMPLE 186-Chloro-2-(4-fluorophenyl)-4-methyl-3,4′-bipyridine-5-carbonitrile

Following a similar procedure to that described in reference example 12,but using2-(4-fluorophenyl)-6-hydroxy-4-methyl-3,4′-bipyridine-5-carbonitrile(obtained in reference example 17) instead of2-(4-fluorophenyl)-6-hydroxy-3,4′-bipyridine-5-carbonitrile, the titlecompound was obtained (yield: 52%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.41 (s, 3H), 6.90 (m, 2H), 7.09 (d,J=9.0 Hz, 2H), 7.25 (m, 2H), 8.62 (m, J=4.0 Hz, 2H).

REFERENCE EXAMPLE 191-(4-Fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone

To a solution of 4-methyl-2-(methylsulfanyl)pyrimidine (21.00 g, 150.0mmol, obtained in reference example 6, section a) and ethyl4-fluorobenzoate (25.14 g, 150.0 mmol) in THF (300 mL) under argonatmosphere, a solution of sodium bis(trimethylsilyl)amide (150 mL of a 2M solution in THF, 300 mmol) in THF (150 mL) was added dropwise whilecooling with an ice-bath. It was stirred at room temperature for 2 h.Saturated NH₄Cl was added and the solvent was evaporated. The residuewas taken up in a mixture of EtOAc and water and the phases wereseparated. The aqueous phase was reextracted with EtOAc. The combinedorganic phases were washed with brine, dried over Na₂SO₄ andconcentrated to dryness, to afford 36.36 g of the title compound (yield:93%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.52 (ketone: s, 3H), 2.61 (enol: s,3H), 4.35 (ketone: s, 2H), 5.92 (enol: s, 1H), 6.64 (enol: d, J=5.7 Hz,1H), 6.95 (ketone: d, J=5.1 Hz, 1H), 7.08-7.19 (m, 2H), 7.83 (enol: m,2H), 8.07 (ketone: m, 2H), 8.31 (enol: d, J=5.7 Hz, 1H), 8.56 (ketone:d, J=5.1 Hz, 1H).

REFERENCE EXAMPLE 203-(Dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one

Following a similar procedure to that described in reference example 7,but using1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone(obtained in reference example 19) instead of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone, the title compound wasobtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.50 (s, 3H), 2.96 (s, 6H), 6.20-8.20(complex signal, 7H).

REFERENCE EXAMPLE 216-(4-Fluorophenyl)-2-(hydroxy)-5-(2-methylsulfanylpyrimidin-4-yl)pyridine-3-carbonitrile

Following a similar procedure to that described in reference example 10,but using3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one(obtained in reference example 20) instead of3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one, thetitle compound was obtained (yield: 91%).

LC-MS (method 1): t_(R)=7.09 min; m/z=338.9 [M+H]⁺

REFERENCE EXAMPLE 222-Chloro-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyridine-3-carbonitrile

A mixture of6-(4-fluorophenyl)-2-(hydroxy)-5-(2-methylsulfanylpyrimidin-4-yl)pyridin-3-carbonitrile(48.84 g, 144.6 mmol, obtained in reference example 21), POCl₃ (166 mL,1.8 mol) and DMF (2.2 mL) was heated to 100° C. for 2 h. It was allowedto cool to room temperature and concentrated. It was cooled with anacetone-CO₂ bath and EtOAc and ice were subsequently added. The organicphase was decanted, washed with saturated NaHCO₃, dried over Na₂SO₄ andconcentrated to dryness. The crude obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity, to afford 31.00 g of the title compound (yield: 60%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.54 (s, 3H), 6.60 (d, J=5.1 Hz, 1H),7.08 (t, J=8.5 Hz, 2H), 7.44 (m; 2H), 8.37 (d, J=5.1 Hz, 1H), 8.39 (s,1H).

REFERENCE EXAMPLE 23 2-(2-Chloropyridin-4-yl)-1-(4-fluorophenyl)ethanone

Following a similar procedure to that described in reference example 19,but starting from 2-chloro-4-methylpyridine and ethyl 4-fluorobenzoate,the title compound was obtained.

LC-MS (method 1): t_(R)=7.96 min; m/z=250.0, 252.0 [M+H]⁺

REFERENCE EXAMPLE 242-[2-(Methylsulfanyl)pyrimidin-4-yl]-1-phenylethanone

Following a similar procedure to that described in reference example 19,but starting from 4-methyl-2-(methylsulfanyl)pyrimidine (obtained inreference example 6, section a) and ethyl benzoate, the title compoundwas obtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.52 (ketone: s, 3H), 2.62 (enol: s,3H), 4.39 (ketone: s, 2H), 5.99 (enol: s, 1H), 6.65 (enol: d, J=5.7 Hz,1H), 6.98 (ketone: d, J=5.1 Hz, 1H), 7.40-7.51 (m, 3H), 7.85 (enol: m,2H), 8.03 (ketone: m, 2H), 8.32 (enol: d, J=5.7 Hz, 1H), 8.46 (ketone:d, J=5.1 Hz, 1H).

REFERENCE EXAMPLE 253-(Dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]-1-phenylprop-2-en-1-one

Following a similar procedure to that described in reference example 7,but starting from 2-[2-(methylsulfanyl)pyrimidin-4-yl]-1-phenylethanone(obtained in reference example 24), the title compound was obtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.50 (s, 3H), 2.90 (s, 6H), 6.20-8.00(complex signal, 8H).

REFERENCE EXAMPLE 262-Hydroxy-5-(2-methylsulfanylpyrimidin-4-yl)-6-phenylpyridine-3-carbonitrile

Following a similar procedure to that described in reference example 10,but using3-(dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]-1-phenylprop-2-en-1-one(obtained in reference example 25) instead of3-dimethylamino-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one, thetitle compound was obtained.

LC-MS (method 1): t_(R)=6.90 min; m/z=320.9 [M+H]⁺

REFERENCE EXAMPLE 271-[6-(4-Fluorophenyl)-2-hydroxy-5-(2-methylsulfanylpyrimidin-4-yl)pyridin-3-yl]ethanone

Following a similar procedure to that described in reference example 10,but starting from3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one(obtained in reference example 20) and 3-oxobutyramide, the titlecompound was obtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.43 (s, 3H), 2.66 (enol: s, 3H), 6.53(d, J=5.1 Hz, 1H), 7.12 (t, J=8.4 Hz, 2H), 7.42 (m, 2H), 8.29 (d, J=5.1Hz, 1H), 8.63 (s, 1H).

REFERENCE EXAMPLES 28-29

Following a similar procedure to that described in reference example 12,but starting from the appropriate compounds in each case, the compoundsin the following table were obtained:

LC-MS Reference Starting t_(R) m/z example Compound name compoundsMethod (min) [M + H]⁺ 28 2-Chloro-5-(2-methylsulfanylpyrimidin-Reference 1 10.18 338.9 4-yl) 6-phenylpyridine-3-carbonitrile example 2629 4-[6-Chloro-5-(1-chlorovinyl)-2-(4- Reference 1 11.62 391.9fluorophenyl)pyridin-3-yl]-2- example 27 393.9 methylsulfanylpyrimidine395.9

REFERENCE EXAMPLE 30 1-(4-Fluorophonyl)-2-pyrimidin-4-ylethanone

To a suspension of NaH (2.26 g 50%, 47.7 mmol) in DMF (92 mL) underargon atmosphere and cooled to 0° C., 4-methylpyrimidine (3.00 g, 31.9mmol) was added slowly. Then, ethyl 4-fluorobenzoate (6.40 g, 38.2 mmol)was added and it was stirred at room temperature overnight. Water wasadded and the solvent was evaporated. The residue was taken up in amixture of EtOAc and brine. The phases were separated and the aqueousphase was reextracted with EtOAc. The combined organic phases were driedover Na₂SO₄ and concentrated to dryness. The crude product obtained bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 3.30 g of the desired compound (yield:48%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.11 (ketone: s, 2H), 5.94 (enol: s,1H), 6.94 (enol: d, J=5.4 Hz, 1H), 7.08-7.16 (m, 2H), 7.37 (ketone: d,J=5.1 Hz, 1H), 7.89 (enol: m, 2H), 8.08 (ketone: m, 2H), 8.42 (enol: d,J=5.4 Hz, 1H), 8.69 (ketone: d, J=5.1 Hz, 1H), 8.81 (enol: s, 1H), 9.17(ketone: s, 1H).

EXAMPLE 14,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine MethodA

In a volumetric flask, 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (23.56g, 109.4 mmol, obtained in reference example 1) and 2-methoxyethanol(150 mL) were introduced. A solution of 3-amino-2H-pyrazole (10.00 g,120.3 mmol) in 2-methoxyethanol (170 mL) and 37% HCl (3.23 g, 32.8 mmol)were added under argon atmosphere. This was heated to reflux for 3 days.It was allowed to cool and concentrated. The solid obtained wasdissolved in CHCl₃ (400 mL) and MeOH (50 mL) and washed with 0.1 N HCl(300 mL) and 1 N NaOH (300 mL). The organic phase was dried over Na₂SO₄and concentrated to dryness, to afford 9.93 g of the desired product insolid cream form (yield: 47%)

Method B

To a solution of 3-amino-2H-pyrazole (60 mg, 71.8 mmol) in EtOH (2 mL)and 1 drop of 37% HCl, 1-(4-fluorophenyl)-2-(4-pyridyl)vinyl4-fluorobenzoate (0.22 g, 65.0 mmol, obtained in reference example 4)was added under argon atmosphere. This was heated to reflux for 3 days.The mixture was diluted with CHCl₃ and MeOH. It was washed withsaturated NaHCO₃. The aqueous phase was extracted with CHCl₃ (×2). Theorganic phase was dried over Na₂SO₄ and concentrated to dryness. Thecrude product obtained was purified by chromatography on silica gelusing hexane-EtOAc mixtures of increasing polarity as eluent, to afford58 mg of the desired product in a solid white form (yield: 23%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.08 (s, NH+CD₃OD), 6.80-7.01(complex signal, 6H), 7.21 (m, 2H), 7.28 (m, 2H), 7.95 (s, 1H), 8.27(dd, J_(o)=1.4 Hz, J_(m)=4.6 Hz, 2H).

EXAMPLE 2 4,6-Diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method B,but using 1-phenyl-2-(4-pyridyl)vinyl benzoate (obtained in referenceexample 5) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)vinyl4-fluorobenzoate, the title compound was obtained in solid white form(yield: 37%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.08 (s, NH+H₂O), 6.85 (d, J=6.0 Hz,2H), 7.12-7.31 (complex signal, 10H), 7.98 (s, 1H), 8.29 (d, J=5.8 Hz,2H).

EXAMPLE 35-(4-Pyridyl)-4,6-bis[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method A,but using 2-(4-pyridyl)-1-[3-(trifluoromethyl)phenyl]ethanone (obtainedin reference example 2) instead of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone, the title compound wasobtained (yield: 10%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (s, NH+H₂O), 6.86 (broad s, 2H),7.30-7.60 (complex signal, 8H), 7.99 (s, 1H), 8.35 (broad s, 2H).

EXAMPLE 44,6-Bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method B,but using 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole,the title compound was obtained in solid white form (yield: 19%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 2.03 (broad s, 3H), 4.08 (s,NH+CD₃OD), 6.81 (m, 2H), 6.96 (m, 2H), 7.01 (m, 2H), 7.04 (m, 2H), 7.29(m, 2H), 8.23 (m, 2H).

EXAMPLE 5 4,6-Diphenyl-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method B,but using 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazoleand 1-phenyl-2-(4-pyridyl)vinyl benzoate (obtained in reference example5) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)vinyl 4-fluorobenzoate,the title compound was obtained in solid white form (yield: 16%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.02 (s, 3H), 2.02 (s, NH+H₂O), 6.83(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.13 (m, 2H), 7.23-7.33 (complexsignal, 6H), 8.25 (83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 62-Ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 71-Ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

A suspension of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.39g, 0.8 mmol, obtained in example 1), KOH (0.05 g, 0.8 mmol) and crownether 18-C-6 (0.01 g, 0.03 mmol) in toluene (3 mL) was heated to 100° C.for 2 h. A solution of iodoethane (0.18 g, 1.2 mmol) in toluene (1 mL)was added and stirred at 100° C. for 2 days. It was allowed to cool,water and EtOAc were added and the phases were separated. The aqueousphase was extracted with EtOAc. The organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 0.20 g of2-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 61%) and 28 mg of1-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 9%).

Example 6: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.68 (t, J=7.4 Hz, 3H), 4.51(c, J=7.2 Hz, 2H), 6.82 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.89 (t,J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.15 (m, 2H), 7.30 (m, 2H), 7.78(s, 1H), 8.31 (dd, J_(o)=1.6 Hz, J_(m)=4.5 Hz, 2H).

Example 7: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61 (t, J=7.4 Hz, 3H), 4.67(c, J=7.2 Hz, 2H), 6.81 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.96 (t,J=8.7 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 7.86(s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 84,6-Bis(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 94,6-Bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 6 and 7, butusing iodomethane instead of iodoethane, the title compounds wereobtained.

Example 8: yield: 52%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.26 (s, 3H),6.81 (d, J=5.3 Hz, 2H), 6.95 (t, J=8.6 Hz, 2H), 6.98 (t, J=8.5 Hz, 2H),7.12 (m, 2H), 7.28 (m, 2H), 7.77 (s, 1H), 8.29 (d, J=5.2 Hz, 2H).

Example 9: yield: 5%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.20 (s, 3H),6.81 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.98(t, J=8.6 Hz, 2H), 7.12 (m, 2H), 7.26 (m, 2H), 7.84 (s, 1H), 8.29 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 104,6-Bis(4-fluorophenyl)-2,3-dimethyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 114,6-Bis(4-fluorophenyl)-1,3-dimethyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 4) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine andiodomethane instead of iodoethane, the title compounds were obtained.

Example 10: yield: 53%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.03 (s, 3H),4.13 (s, 3H), 6.79 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.88 (t, J=8.8Hz, 2H), 6.98-7.11 (complex signal, 4H), 7.30 (m, 2H), 8.26 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 11: yield: 30%; ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 2.01(broad s, 3H), 4.15 (broad s, 3H), 6.81 (m, 2H), 6.93 (m, 2H), 7.00 (m,2H), 7.07 (m, 2H), 7.30 (m, 2H), 8.23 (m, 2H).

EXAMPLE 122-[2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]ethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 131-[2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]ethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridinea) 2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]ethanol

To a solution of 2-(4-piperidyl)ethanol (9.63 g, 74.5 mmol) in DMF (100mL) at 0° C., di-tert-butyl dicarbonate (16.26 g, 74.5 mol) was addedslowly. The mixture was stirred overnight at room temperature. Thesolvent was concentrated and the residue was dissolved in a mixture ofEtOAc and water. The phases were separated. The organic phase was driedover Na₂SO₄ and concentrated to dryness, to afford 15.09 g of thedesired product (yield: 88%).

b) 2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]ethyl methanesulfonate

To a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethanol (7.50g, 32.7 mmol, obtained in section a) in CHCl₃ (180 mL), triethylamine(4.6 mL) was added under argon atmosphere and cooled to 0° C. Then,methanesulfonyl chloride (2.6 mL, 32.7 mmol) was added dropwise. Themixture was stirred overnight at room temperature. Water was added andthe phases were separated. The aqueous phase was extracted with CHCl₃(×3). The organic phase was dried over Na₂SO₄ and concentrated todryness, to afford 11.18 g of the desired compound (yield:quantitative).

c) Title Compounds

Following a similar procedure to that described in example 6 and 7, butusing 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl methanesulfonate(obtained in section b) instead of iodoethane, the title compounds wereobtained.

Example 12: yield: 14%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.00-1.40(complex signal, 3H), 1.45 (s, 9H), 1.70 (m, 2H), 2.66 (m, 2H), 2.05 (m,2H), 4.09 (m, 2H), 4.90 (t, J=7.4 Hz, 2H), 6.83 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.14(m, 2H), 7.28 (m, 2H), 7.77 (s, 1H), 8.31 (dd, J_(o)=1.6 Hz, J_(m)=4.4Hz, 2H).

Example 13: yield: 29%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.00-1.40(complex signal, 3H), 1.46 (s, 9H), 1.82 (m, 2H), 1.98 (m, 2H), 2.67 (m,2H), 4.08 (m, 2H), 4.65 (t, J=7.0 Hz Hz, 2H), 6.82 (dd, J_(o)=1.6 Hz,J_(m)=4.5 Hz, 2H), 6.93 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 7.25(m, 2H), 7.28 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 142-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 151-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridinea) 1-(tert-Butoxycarbonyl)piperidin-4-yl methanesulfonate

Following a similar procedure to that described in examples 12 and 13section b, but using (1-tert-butoxycarbonyl)piperidin-4-ol instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethanol, the desired compoundwas obtained (yield: 97%).

b) Title Compounds

Following a similar procedure to that described in examples 6 and 7, butusing4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 4) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate (obtained insection a) instead of iodoethane, the title compounds were obtained.

Example 14: yield: 13%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.51 (s, 9H),1.97 (m, 2H), 2.06 (s, 3H), 2.45 (m, 2H), 2.94 (m, 2H), 4.35 (m, 3H),6.78 (d, J=6.0 Hz, 2H), 6.87 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H),7.10 (m, 2H), 7.33 (m, 2H), 8.26 (d, J=6.0 Hz, 2H).

Example 15: yield: 52%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.54 (s, 9H),2.00 (s, 3H), 2.00 (m, 2H), 2.31 (m, 2H), 2.99 (m, 2H), 4.33 (m, 2H),5.10 (m, 1H), 6.78 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7 Hz, 2H), 7.08 (m, 2H), 7.30 (m, 2H), 8.27 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 162-(3-Chloropropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 171-(3-Chloropropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 1-bromo-3-chloropropane instead of iodoethane, the title compoundswere obtained.

Example 16: yield: 28%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.54 (m, 2H),3.52 (t, J=6.0 Hz, 2H), 4.61 (t, J=6.0 Hz, 2H), 6.81 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 6.86 (t, J=8.8 Hz, 2H), 6.98 (t, J=8.7 Hz, 2H), 7.13(m, 2H), 7.28 (m, 2H), 7.83 (s, 1H), 8.29 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

Example 17: yield: 19%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.51 (m, 2H),3.61 (t, J=6.3 Hz, 2H), 4.78 (t, J=6.4 Hz, 2H), 6.82 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 6.92 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 7.14(m, 2H), 7.26 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J_(o)=1.6 Hz, J_(m)=4.4Hz, 2H).

EXAMPLE 183-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pirridin-2-yl]propan-1-olMethod A a)4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-2-[3-(tetrahydropyran-2-yloxy)propyl]pyrazolo[3,4-b]pyridine

A suspension of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30g, 0.8 mmol, obtained in example 1), KOH (0.05 g, 0.8 mmol) and crownether 18-C-6 (0.01 g, 0.03 mmol) in toluene (10 mL) was heated to 100°C. for 1 h. 2-(3-Bromopropoxy)tetrahydropyran (0.17 g, 0.8 mmol) wasadded and stirred at 100° C. for 24 h. It was allowed to cool, water andEtOAc were added and the phases were separated. The aqueous phase wasextracted with EtOAc. The organic phase was dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 0.22 g of the desired compound (yield:54%).

LC-MS (método 1): t_(R)=7.60 min; m/z=527.2 [M+H]⁺.

b) Title Compound

A solution of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-[3-(tetrahydropyran-2-yloxy)propyl]pyrazolo[3,4-b]pyridine(0.22 g, 0.42 mmol, obtained in section a) in a mixture 4:2:1 ofAcOH:THF:H₂O (9 mL) was heated to a 55° C. for 3 h. It was allowed tocool and concentrated. Saturated NaHCO₃ and 1 N NaOH were added to theresidue and it was extracted with EtOAc. The organic phase was driedover Na₂SO₄ and concentrated to dryness, to afford 0.15 g of the titlecompound (yield: 83%).

LC-MS (método 1): t_(R)=5.37 min; m/z=−443.1 [M+H]⁺.

EXAMPLE 183-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pirridin-2-yl]propan-1-olEXAMPLE 193-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propan-1-olMethod B

Following a similar procedure to that described in examples 6 and 7, butusing 3-iodopropanol instead of iodoethane, the title compounds wereobtained.

Example 18: yield: 33%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.58 (s,OH+H₂O), 2.17 (m, 2H), 3.71 (m, 2H), 4.63 (t, J=6.4 Hz, 2H), 6.83 (dd,J_(o)=1.6 Hz, J=4.4 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz,2H), 7.15 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H), 8.33 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

Example 19: yield: 21%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (s,OH+H₂O), 2.17 (m, J=5.9 Hz, 2H), 3.58 (m, 2H), 4.78 (t, J=6.0 Hz, 2H),6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.94 (t, J=8.7 Hz, 2H), 7.02(t, J=8.7 Hz, 2H), 7.15 (m, 2H), 7.27 (m, 2H), 7.90 (s, 1H), 8.34 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 202-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 211-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following an analogous procedure to that described in examples 6 and 7,but using 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate(obtained in example 14 section a) instead of iodoethane, the titlecompounds were obtained.

Example 20: yield: 30%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.48 (s, 9H),2.00-2.20 (m, 4H), 2.87 (m, 2H), 4.21 (m, 2H), 4.50 (m, 1H), 6.73 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.81 (t, J=8.7 Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.03 (m, 2H), 7.20 (m, 2H), 7.73 (s, 1H), 8.23 (dd, J_(o)=1.4Hz, J_(m)=4.4 Hz, 2H).

Example 21: yield: 28%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.46 (s, 9H),2.10-2.30 (complex signal, 4H), 2.96 (m, 2H), 4.30 (m, 2H), 4.60 (m,1H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H),7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.31 (m, 2H), 7.82 (s, 1H), 8.31(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 22 2-Methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 23 1-Methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

To a suspension of 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.10 g, 0.3 mmol, obtained in example 2) in acetone (1 mL), KOH (21 mg,0.4 mmol) was added under argon atmosphere. Then, a solution ofiodomethane (47 mg, 0.3 mmol) in acetone (0.1 mL) was added and stirredovernight at room temperature. Water was added and extracted with CHCl₃.The organic phase was dried over Na₂SO₄ and concentrated to dryness. Thecrude product obtained was purified by chromatography on silica gelusing hexane-EtOAc mixtures of increasing polarity as eluent, to afford47 mg of 2-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 47%) and 38 mg of1-methyl-4,6-diphenyl-5-(4-pirridyl)pyrazolo[3,4-b]pyridine (yield:38%).

Example 22: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.24 (s, 3H), 6.83 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.16-7.21 (complex signal, 4H),7.26-7.31 (complex signal, 6H), 7.77 (s, 1H), 8.24 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

Example 23: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.23 (s, 3H), 6.81 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 7.17 (m, 2H), 7.22-7.32 (complexsignal, 8H), 7.89 (s, 1H), 8.26 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 244,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-2-[2-(tetrahydropiran-2-yloxy)ethyl]pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 2-(2-bromoethoxy)tetrahydropyran instead of iodoethane, the titlecompound was obtained (yield: 50%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.48-1.63 (complex signal, 6H), 3.47(m, 1H), 3.67 (m, 1H), 4.02 (m, 1H), 4.22 (m, 1H), 4.57 (m, 1H), 4.65(m, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz,2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.31 (m, 2H), 7.92 (s, 1H),8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 252-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]ethanol

Following a similar procedure to that described in examples 22 and 23,but using

4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 1) instead of4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and 2-bromoethanolinstead of iodomethane, the title compound was obtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.19 (m, 2H), 4.32 (m, OH), 4.77 (t,J=4.7 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 7.02 (t, J=8.6 Hz, 2H), 7.15 (m, 2H), 7.26 (m, 2H), 7.89 (s,1H), 8.34 (dd, J_(o)=1.6 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 264,6-Bis(4-fluorophenyl)-2-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 274,6-Bis(4-fluorophenyl)-1-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridinea) 1-Chloromethyl-4-(methylsulfanyl)benzene

A solution of thionyl chloride (0.2 mL, 3.2 mmol) in THF (9 mL) wasadded slowly to 4-(methylsulfanylphenyl)methanol (0.346 g, 2.2 mmol)under argon atmosphere. The mixture was stirred at room temperature for2 days. Brine (9 mL) was added and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated to dryness, toafford 0.37 g of the desired compound (yield: 95%).

b) Title Compounds

In a volumetric flask,4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30g, 78.0 mmol, obtained in example 1) and DMF (3.5 mL) were introducedunder argon atmosphere. KOH (0.06 g, 1.1 mmol) was added followed by asolution of 1-chloromethyl-4-(methylsulfanyl)benzene (0.15 g, 0.9 mmol,obtained in section a) in DMF (0.4 mL). This was heated to 60° C.overnight. It was allowed to cool and concentrated. The residue wasdissolved in a mixture of water and EtOAc. The two phases wereseparated. The organic phase was dried over Na₂SO₄ and concentrated todryness. The crude product obtained was purified by chromatography onsilica gel using hexane-EtOAc mixtures of increasing polarity as eluent,to afford 0.10 g of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 25%) and 0.19 g of4,6-bis(4-fluorophenyl)-1-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 47%).

Example 26: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.50 (s, 3H), 5.60 (s, 2H),6.84 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.92 (t, J=8.8 Hz, 2H), 7.00(t, J=8.7 Hz, 2H), 7.05 (m, 2H), 7.24-7.37 (complex signal, 6H), 7.76(s, 1H), 8.34 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 27: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.49 (s, 3H), 5.77 (s, 2H),6.85 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.97 (t, J=8.8 Hz, 2H), 7.03(t, J=8.7 Hz, 2H), 7.15 (m, 2H), 7.24-7.33 (complex signal, 4H), 7.42(d, J=8.1 Hz, 2H), 7.89 (s, 1H), 8.36 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz,2H).

EXAMPLE 282-[1-(tert-Butoxycarbonyl)piperidin-4-ylmethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 291-[1-(tert-Butoxycarbonyl)piperidin-4-ylmethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridinea) (4-Piperidyl)methanol

To a suspension of LiAlH₄ (10.10 g, 0.266 mol) in THF (150 mL) at 0° C.,a solution of ethyl piperidine-4-carboxylate (18.13 g, 0.120 mol) in THF(300 mL) was added slowly. This was stirred at room temperatureovernight. It was cooled with an ice bath and a mixture of water (14 mL)and THF (28 mL) was added slowly. Afterwards, a mixture of 15% aqueousNaOH (14 mL) and water (37 mL) was added followed by stirring at roomtemperature for 30 min. The precipitate obtained was filtered and thefiltrate was concentrated, to afford 17.88 g of the desired compound(yield: quantitative).

b) [1-(tert-Butoxycarbonyl)piperidin-4-yl]methanol

Following a similar procedure to that described in Example 12 section a,but using (4-piperidyl)methanol (obtained in section a of this example),instead of 2-(4-piperidyl)ethanol, the title compound was obtained(yield: 77%).

c) [1-(tert-Butoxycarbonyl)piperidin-4-yl]methyl methanesulfonate

Following a similar procedure to that described in example 12 section b,but using [1-(tert-butoxycarbonyl)piperidin-4-yl]methanol (obtained insection b of this example) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethanol, the title compound wasobtained (yield: 71%).

d) Title Compounds

Following a similar procedure to that described in examples 26 and 27,but using [1-(tert-butoxycarbonyl)piperidin-4-yl]methyl methanesulfonate(obtained in section c) instead of1-chloromethyl-4-(methylsulfanyl)benzene, the title compounds wereobtained.

Example 28: yield: 22%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.47 (s, 9H),1.63 (m; 2H), 2.43 (m, 1H), 2.72 (m, 2H), 4.15 (m, 2H), 4.33 (d, J=7.2Hz, 2H), 6.86 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.93 (t, J=8.7 Hz,2H), 7.04 (t, J=8.7 Hz, 2H), 7.17 (m, 2H), 7.33 (m, 2H), 7.77 (s, 1H),8.35 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 29: yield: 71%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.20-1.8(complex signal, 5H), 1.49 (s, 9H), 2.35 (m, 1H), 2.74 (m, 2H), 4.15 (m,2H), 4.54 (d, J=7.2 Hz, 2H), 6.86 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H),6.97 (t, J=8.7 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 7.18 (m, 2H), 7.28 (m,2H), 7.90 (s, 1H), 8.36 (dd, J_(o)=1.6 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 304,6-Bis(4-fluorophenyl)-2-[2-(morpholin-4-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 314,6-Bis(4-fluorophenyl)-1-[2-(morpholin-4-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 26 and 27,but using 4-(2-chloroethyl)morpholine hydrochloride, instead of1-chloromethyl-4-(methylsulfanyl)benzene and 2 equivalents of KOH, thetitle compounds were obtained.

Example 30: yield: 10%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.55 (m, 4H),3.06 (t, J=6.4 Hz, 2H), 3.70 (m, 4H), 4.58 (t, J=6.4 Hz, 2H), 6.86 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.93 (t, J=8.9 Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.16 (m, 2H), 7.31 (m, 2H), 7.88 (s, 1H), 8.35 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H).

Example 31: yield: 24%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.63 (m, 4H),3.04 (t, J=6.9 Hz, 2H), 3.69 (m, 4H), 4.77 (t, J=6.8 Hz, 2H), 6.86 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H), 7.05 (t, J=8.7Hz, 2H), 7.18 (m, 2H), 7.28 (m, 2H), 7.90 (s, 1H), 8.36 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 32 Ethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetateEXAMPLE 33 Ethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]acetate

Following a similar procedure to that described in examples 26 and 27,but using ethyl bromoacetate instead of1-chloromethyl-4-(methylsulfanyl)benzene, the title compounds wereobtained.

Example 32: yield: 6%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.32 (t, J=7.2Hz, 3H), 4.32 (c, J=7.2 Hz, 2H), 5.27 (s, 2H), 6.86 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 6.93 (t, J=8.7 Hz, 2H), 7.03 (t, J=8.6 Hz, 2H), 7.18(m, 2H), 7.32 (m, 2H), 7.93 (s, 1H), 8.35 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

Example 33: yield: 21%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.32 (t, J=7Hz, 3H), 4.31 (c, J=6.9 Hz, 2H), 5.42 (s, 2H), 6.84 (dd, J_(o)=1.6 Hz,J_(m)=4.5 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 7.05 (t, J=8.7 Hz, 2H), 7.19(m, 2H), 7.28 (m, 2H), 7.98 (s, 1H), 8.36 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 34 Ethyl3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propionateEXAMPLE 35 Ethyl3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionate

Following a similar procedure to that described in examples 26 and 27,but using ethyl 3-bromopropionate instead of1-chloromethyl-4-(methylsulfanyl)benzene, the title compounds wereobtained.

Example 34: yield: 5%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.26 (t, J=7.2Hz, 3H), 3.20 (t, J=6.3 Hz, 2H), 4.31 (c, J=7.2 Hz, 2H), 4.76 (t, J=6.3Hz, 2H), 6.85 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.93 (t, J=8.8 Hz,2H), 7.03 (t, J=8.5 Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.92 (s, 1H),8.34 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 35: yield: 3%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.25 (t, J=7.2Hz, 3H), 3.10 (t, J=7.2 Hz, 2H), 4.17 (c, J=7.1 Hz, 2H), 4.94 (t, J=7.0Hz, 2H), 6.85 (dd, J_(o)=1.6 Hz, J_(m)=4.6 Hz, 2H), 6.96 (t, J=8.6 Hz,2H), 7.04 (t, J=8.6 Hz, 2H), 7.18 (m, 2H), 7.31 (m, 2H), 7.89 (s, 1H),8.36 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 364,6-Bis(4-fluorophenyl)-2-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

To a solution of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.62 g, 1.1 mmol, obtained in example 20) in CH₂Cl₂ (19 mL) under argonatmosphere and cooled to 0° C., trifluoroacetic acid (1.8 mL) was added.It was stirred at room temperature for 2.5 h. The solvent wasevaporated. The residue was dissolved in CHCl₃ and washed with 1 N NaOHand brine. The organic phase was dried over Na₂SO₄ and concentrated todryness, to afford 319 mg of the title compound (yield: 62%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.71 (broad s, NH+H₂O), 2.21 (m, 2H),2.34 (m, 2H), 2.88 (m, 2H), 3.35 (m, 2H), 4.54 (m, 1H), 6.87 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 7.06 (t, J=8.6Hz, 2H), 7.18 (m, 2H), 7.34 (m, 2H), 7.88 (s, 1H), 8.36 (dd, J_(o)=1.6Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 374,6-Bis(4-fluorophenyl)-1-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 21) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 29%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.62 (broad s, NH+H₂O), 2.13 (m, 2H),2.32 (m, 2H), 2.92 (m, 2H), 3.33 (m, 2H), 4.52 (m, 1H), 6.81 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.94 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.27 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J_(o)=1.4Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 384,6-Bis(4-fluorophenyl)-2-(4-piperidylmethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using2-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 28) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 13%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.30-1.80 (complex signal, 4H), 1.63(broad s, NH+H₂O), 2.38 (m, 1H), 2.64 (m, 2H), 3.14 (m, 2H), 4.32 (d,J=7.2H), 6.86 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.93 (t, J=8.8 Hz,2H), 7.04 (t, J=8.6 Hz, 2H), 7.18 (m, 2H), 7.33 (m, 2H), 7.78 (s, 1H),8.35 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 394,6-Bis(4-fluorophenyl)-1-(4-piperidylmethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 29) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 12%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.80-2.10 (complex signal, 4H), 2.47(m, 1H), 3.0 (m, 3H), 3.50 (m, 2H), 4.63 (d, J=6.6, 2H), 7.04 (t, J=8.4Hz, 2H), 7.12-7.16 (complex signal, 4H), 7.22 (m, 2H), 7.31 (m, 2H),7.95 (s, 1H), 8.58 (d, J=6.6, 2H).

EXAMPLE 404,6-Bis(6-chloropyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method A,but using 1-(6-chloropyridin-3-yl)-2-(4-pyridyl)ethanone (obtained inreference example 9) instead of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone, the title compound wasobtained (yield: 17%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 6.90 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz,2H), 7.21 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.38 (dd, J_(o)=2.5Hz, J_(m)=8.3 Hz, 1H), 7.49 (dd, J_(o)=2.4 Hz, J_(m)=8.4 Hz, 1H), 8.00(s, 1H), 8.36 (d, J=2.4 Hz, 1H), 8.46-8.48 (complex signal, 3H), 11.34(broad s, 1H).

EXAMPLE 414,6-Bis(4-fluorophenI)-3-methyl-2-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 14) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 73%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.55 (broad s, NH+H₂O), (s, 3H), 2.35(m, 2H), 3.34 (m, 2H), 3.85 (m, 2H), 4.73 (m, 2H), 4.75 (m, 1H), 6.78(d, J=6.3 Hz, 2H), 6.89 (t, J=8.6 Hz, 2H), 7.03-7.19 (complex signal,4H), 7.29 (m, 2H), 8.27 (d, J=6.0 Hz, 2H).

EXAMPLE 424,6-Bis(4-fluorophenyl)-3-methyl-1-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-3-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 15) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 59%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.55 (broad s, NH+H₂O), 2.01 (s, 3H),2.07 (m, 2H), 2.29 (m, 2H), 2.90 (m, 2H), 3.32 (m, 2H), 4.75 (m, 1H),6.78 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.93 (t, J=8.7 Hz, 2H), 6.99(t, J=8.7 Hz, 2H), 7.08 (m, 2H), 7.30 (m, 2H), 8.27 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H).

EXAMPLE 434,6-Bis(4-fluorophenyl)-2-[2-(4-piperidyl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 12) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 88%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.00-1.60 (complex signal, 3H), 1.66(s, NH+H₂O), 1.74 (m, 2H), 2.03 (m, 2H), 2.60 (m, 2H), 3.10 (m, 2H),4.85 (t, J=7.2 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89(t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.30 (m, 2H),7.76 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 442-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid

To a solution of ethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetate(0.09 g, 0.2 mmol, obtained in example 32) in EtOH (4.2 mL), a solutionof KOH (0.09 g, 2.5 mmol) in water (0.5 mL) was added. This was heatedto reflux for 1 h. It was allowed to cool and concentrated. The residuewas dissolved in a mixture of EtOAc and water. The phases wereseparated. The aqueous phase was acidified and extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄ and concentrated todryness, to afford 57 mg of title compound (yield: 66%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.00 (broad s, 1H+ CD₃OD), 5.28(broad s, 2H), 6.92-7.05 (complex signal, 6H), 7.15-7.30 (complexsignal, 4H), 8.02 (broad s, 1H), 8.26 (m, 2H).

EXAMPLE 452-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]aceticacid

Following a similar procedure to that described in example 44, but usingethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]acetate(obtained in example 33) instead of ethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetate,the title compound was obtained (yield: 96%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 3.88 (broad s, 1H+ CD₃OD), 5.32(s, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.88 (t, J=8.7 Hz,2H), 6.98 (t, J=8.6 Hz, 2H), 7.11 (m, 2H), 7.20 (m, 2H), 7.90 (s, 1H),8.21 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 463-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propionicacid

Following a similar procedure to that described in example 44, but usingethyl3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propionate(obtained in example 34) instead of ethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetate,the title compound was obtained (yield: 69%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 3.08 (t, J=6.3 Hz, 2H), 4.50(broad s, 1H+CD₃OD), 4.72 (t, J=6.3 Hz, 2H), 6.88 (dd, J_(o)=1.6 Hz,J_(m)=4.6 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.99 (t, J=8.7 Hz, 2H), 7.15(m, 2H), 7.23 (m, 2H), 8.03 (s, 1H), 8.21 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 473-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionicacid

Following a similar procedure to that described in example 44, but usingethyl3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionate(obtained in example 35) instead of ethyl2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetate,the title compound was obtained (yield: 88%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 3.02 (t, J=7.2 Hz, 2H), 4.50(broad s, 1H+ CD₃OD), 4.86 (t, J=7.3 Hz, 2H), 6.87 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 6.91 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.12(m, 2H), 7.24 (m, 2H), 7.84 (s, 1H), 8.21 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 482-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-1-(morpholin-4-yl)ethanone

To a solution of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid (0.05 g, 0.1 mmol, obtained in example 44) in DMF (1 mL),N,N′-dicyclohexylcarbodiimide (0.02 g, 0.1 mmol) and1-hydroxybenzotriazole (0.02 g, 0.1 mmol) were added under argonatmosphere. The mixture was stirred for 15 min and morpholine (0.01 g,0.1 mmol) was added. This was stirred at room temperature for 2 days.EtOAc was added and the mixture was filtered. The filtrate was washedwith saturated NaHCO₃. The organic phase was dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using EtOAc-MeOH mixtures of increasingpolarity as eluent, to afford 18 mg of title compound (yield: 35%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.66-3.76 (complex signal, 8H), 5.30(s, 2H), 6.82 (d, J=5.7 Hz, 2H), 6.91 (t, J=8.8 Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.99 (s, 1H), 8.32 (d, J=6.0 Hz,2H).

EXAMPLE 492-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]acetamide

Following a similar procedure to that described in example 48, but using2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]aceticacid (obtained in example 45) instead of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid, and aqueous NH₃ instead of morpholine, the title compound wasobtained (yield: 36%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.35 (s, 2H), 5.56 (broad s, 1H), 6.15(broad s, 1H), 6.85 (d, J=5.4 Hz, 2H), 6.96 (t, J=8.6 Hz, 2H), 7.06 (t,J=8.6 Hz, 2H), 7.17 (m, 2H), 7.29 (m, 2H), 8.01 (s, 1H), 8.38 (d, J=5.4Hz, 2H).

EXAMPLE 502-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-1-(morpholin-4-yl)ethanone

Following a similar procedure to that described in example 48, but using2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]aceticacid (obtained in example 45) instead of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid, the title compound was obtained (yield: 60%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.67-3.70 (complex signal, 4H),3.75-3.81 (complex signal, 4H), 5.50 (s, 2H), 6.83 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 7.17(m, 2H), 7.27 (m, 2H), 7.99 (s, 1H), 8.35 (dd, J_(o)=1.6 Hz, J_(m)=4.4Hz, 2H)

EXAMPLE 513-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-1-(morpholin-4-yl)propan-1-one

Following a similar procedure to that described in example 48, but using3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propionicacid (obtained in example 46) instead of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid, the title compound was obtained (yield: 64%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.20 (t, J=6.0 Hz, 2H), 3.45 (m, 2H),3.55-3.63 (complex signal, 6H), 4.79 (t, J=6.1 Hz, 2H), 6.81 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.30 (m, 2H), 7.94 (s, 1H), 8.31 (dd, J_(o)=1.6Hz, J_(m)=4.4 Hz, 2H)

EXAMPLE 523-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-N-propylpropionamide

Following a similar procedure to that described in example 48, but using3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionicacid (obtained in example 47) instead of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid, and propylamine instead of morpholine, the title compound wasobtained (yield: 76%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 0.84 (t, J=7.3 Hz, 3H), 1.42 (m, 2H),2.98 (t, J=6.7 Hz, 2H), 3.18 (m, 2H), 4.95 (t, J=6.7 Hz, 2H), 6.05 (m,NH), 6.84 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H),7.04 (t, J=8.7 Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.89 (s, 1H), 8.36(dd, J=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 533-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-1-(morpholin-4-yl)propan-1-one

Following a similar procedure to that described in example 48, but using3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionicacid (obtained in example 47) instead of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid, the title compound was obtained (yield: 72%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.13 (t, J=7.3 Hz, 2H), 3.49 (m, 2H),3.63-3.67 (complex signal, 6H), 4.99 (t, J=7.3 Hz, 2H), 6.84 (dd,J_(o)=1.4 Hz, J_(m)=4.4 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.16 (m, 2H), 7.30 (m, 2H), 7.89 (s, 1H), 8.36 (dd, J_(o)=1.6Hz, J_(m)=4.4 Hz, 2H)

EXAMPLE 544,6-Bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 554,6-Bis(4-fluorophenyl)-1-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

In a volumetric flask molecular sieves of 4 Å (1 g, previously dried for3 h at 200° C. under vacuum),4±6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30g, 0.8 mmol, obtained in example 1), (4-methylsulfanylphenyl)boronicacid (0.26 g, 1.6 mmol), copper II acetate (0.28 g, 1.6 mmol), pyridine(0.12 g, 1.6 mmol), triethylamine (0.16 g, 1.6 mmol) and CH₂Cl₂ (22 mL)were introduced under argon atmosphere. This was stirred at roomtemperature for 2 days. It was filtered through celite and concentrated.The crude product obtained was purified by chromatography on silica gelusing hexane-EtOAc mixtures of increasing polarity as eluent, to afford40 mg of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 10%) and 90 mg of4,6-bis(4-fluorophenyl)-1-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 23%).

Example 54: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.46 (s, 3H), 6.76 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.83 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.6Hz, 2H), 7.11 (m, 2H), 7.26 (m, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.83 (d,J=8.7 Hz, 2H), 8.16 (s, 1H), 8.26 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 55: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.46 (s, 3H), 6.76 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.86 (t, J=8.7 Hz, 2H), 6.96 (t, J=8.7Hz, 2H), 7.08 (m, 2H), 7.22 (m, 2H), 7.34 (d, J=9.0 Hz, 2H), 7.94 (s,1H), 8.23 (d, J=8.7 Hz, 2H), 8.26 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 564,6-Bis(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 574,6-Bis(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

To a solution of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.09 g, 0.2 mmol, obtained in example 54) in CH₂Cl₂ (3.5 mL),3-chloroperbenzoic acid (0.04 g, 0.2 mmol) was added under argonatmosphere and stirred for 2 h at room temperature. CHCl₃ was added andwashed with saturated NaHCO₃. The organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product obtained was purified bychromatography on silica gel using increasing polarity hexane-EtOAcmixtures as eluent, to afford 15 mg of4,6-bis(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 16%) and 10 mg of4,6-bis(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 11%)

Example 56: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.83 (s, 3H), 6.90 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H), 7.08 (t, J=8.7Hz, 2H), 7.24 (m, 2H), 7.36 (m, 2H), 7.75 (HA from an AB system, J=8.9Hz, 2H), 8.32 (HB from an AB system, J=8.9 Hz, 2H), 8.38 (s, 1H), 8.39(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 57: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.16 (s, 3H), 6.89 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.97 (t, J=8.7 Hz, 2H), 7.09 (t, J=8.7Hz, 2H), 7.24 (m, 2 H), 7.36 (m, 2H), 8.05 (HA from an AB system, J=9.0Hz, 2H), 8.38 (HB from an AB system, J=9.0 Hz, 2H), 8.39 (dd, J_(o)=1.6Hz, J_(m)=4.6 Hz, 2H), 8.41 (s, 1H).

EXAMPLE 584,6-Bis(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 56, but using4,6-bis(4-fluorophenyl)-1-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 55) instead of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 70%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.82 (s, 3H), 6.90 (dd, J_(o)=1.8 Hz,J_(m)=4.5 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.09 (t, J=8.6 Hz, 2H), 7.20(m, 2H), 7.35 (m, 2H), 7.86 (dd, J_(o)=2.1 Hz, J_(m)=6.9 Hz, 2H), 8.10(s, 1H), 8.41 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 8.69 (dd, J_(o)=1.8Hz, J_(m)=6.9 Hz, 2H).

EXAMPLE 594,6-Bis(4-fluorophenyl)-2-(4-methylsulfinylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 604,6-Bis(4-fluorophenyl)-2-(4-methylsulfonylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 56, but using4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 26) instead of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compounds were obtained.

Example 59: yield: 48%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.74 (s, 3H),5.70 (s, 2H), 6.85 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.93 (t, J=8.8Hz, 2H), 7.02 (t, J=8.7 Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.59 (HAfrom an AB system, J=8.2 Hz, 2H), 7.68 (HB from an AB system, J=8.2 Hz,2H), 7.87 (s, 1H), 8.39 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 60: yield: 16%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.07 (s, 3H),5.73 (s, 2H), 6.85 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.03 (t, J=8.8 Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.61 (HAfrom an AB system, J=8.7 Hz, 2H), 7.89 (s, 1H), 7.97 (HB from an ABsystem, J=8.7 Hz, 2H), 8.36 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 614,6-Bis(4-fluorophenyl)-1-(4-methylsulfinylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 624,6-Bis(4-fluorophenyl)-1-(4-methylsulfonylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 56, but using4,6-bis(4-fluorophenyl)-1-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 27) instead of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compounds were obtained.

Example 61: yield: 69%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.71 (s, 3H),5.84 (s, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.94 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 7.13 (m, 2H), 7.25 (m, 2H), 7.61 (HAfrom an AB system, J=8.4 Hz, 2H), 7.92 (HB from an AB system, J=8.4 Hz,2H), 7.91 (s, 1H), 8.34 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 62: yield: 4%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.03 (s, 3H),5.87 (s, 2H), 6.83 (d, J=6.0 Hz, 2H), 6.94 (t, J=8.8 Hz, 2H), 7.02 (t,J=8.7 Hz, 2H), 7.14 (m, 2H), 7.26 (m, 2H), 7.60 (HA from an AB system,J=8.2 Hz, 2H), 7.91 (s, 1H), 7.93 (HB from an AB system, J=8.2 Hz, 2H),8.34 (d, J=6.3 Hz, 2H).

EXAMPLE 633-Chloro-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

To a solution of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20g, 0.5 mmol, obtained in example 1) in DMF (5 mL), N-chlorosuccinimide(0.10 g, 0.8 mmol) was added under argon atmosphere and the mixture washeated to 60° C. for 5 h. It was washed with 1 N NaOH and extracted withCHCl₃ and EtOAc. The combined organic phases were dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 171 mg of title compound (yield: 79%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61 (broad s, NH+H₂O), 6.82 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.98 (t, J=8.7 Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 8.35 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 643-Bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

To a suspension of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (1.00g, 2.6 mmol, obtained in example 1) in CHCl₃ (10 mL), a solution of Br₂(0.69 g, 4.3 mmol) in CHCl₃ (3 mL) was added under argon atmosphere.Acetonitrile (4 mL) was added and the mixture was stirred at roomtemperature for 2 days. The residue was concentrated, dissolved in CHCl₃and washed with 1 N NaOH. A precipitate was formed, which was filteredand dissolved with MeOH. The solution was concentrated and washed with 1N NaOH. It was extracted with EtOAc, dried over Na₂SO₄ and concentrated.This was treated with diethyl ether, the solvent was decanted and theproduct obtained was dried to afford 1.16 g of the title compound(yield: 97%).

¹H NMR (300 MHz, CD₃OD) δ (TMS): 4.78 (broad s, NH+CD₃OD), 6.89 (t,J=8.8 Hz, 2H), 6.93-6.99 (complex signal, 4H), 7.14 (m, 2H), 7.27 (m,2H), 8.12 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 654,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

In a volumetric flask,3-bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.20 g, 0.4 mmol, obtained in example 64), copper cyanide (I) (0.05 g,0.6 mmol) and anhydrous 1-methyl-2-pyrrolidone (1 mL) were introducedunder argon atmosphere and heated to reflux for 2 h. This was pouredinto a 10% aqueous solution of ethylendiamine (4 mL) and extracted withCHCl₃. Brine was added to the aqueous phase and it was extracted withEtOAc. The combined organic phases were dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford the title compound in a solid form (yield:quantitative).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.00 (broad s, NH+CD₃OD),6.80-7.40 (complex signal, 12H), 8.25 (m, 2H).

EXAMPLE 663-Bromo-4,6-bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 64, but using4,6-bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 9) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine, thetitle compound was obtained (yield: 15%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.21 (s, 3H), 6.78 (d, J=6.0 Hz, 2H),6.93-7.02 (complex signal, 4H), 7.08 (m, 2H), 7.27 (m, 2H), 8.29 (d,J=6.0 Hz, 2H).

EXAMPLE 674,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A solution of KOH (0.07 g, 1.3 mmol) in tBuOH (2.5 mL) was added underargon atmosphere to4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(0.05 g, 0.1 mmol, obtained in example 65) and heated to refluxovernight. Water and EtOAc were added and the phases were separated. Theaqueous phase was extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and concentrated to dryness. The crude productobtained was purified by chromatography on silica gel using hexane-EtOAcmixtures of increasing polarity as eluent, to afford 15 mg of the titlecompound in solid form (yield: 28%)

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (broad s, NH₂+H₂O), 6.80 (d, J=4.5Hz, 2H), 6.90-7.10 (complex signal, 6H), 7.30 (m, 2H), 8.30 (d, J=4.5Hz, 2H).

EXAMPLE 683-Aminomethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

LiAlH₄ (0.06 g, 1.5 mmol) and anhydrous diethyl ether (2 mL) wereintroduced into a volumetric flask. The mixture was cooled with an icebath and a solution of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(0.15 g, 0.4 mmol, obtained in example 65) in diethyl ether (1 mL) wasadded dropwise. THF (2 mL) was added and the mixture was stirred at roomtemperature overnight. It was cooled with an ice bath and successivelywater (0.1 mL), THF (0.2 mL), a 15% aqueous NaOH (0.1 mL) and water (0.3mL) were added. The precipitate obtained was filtered and washed withTHF. The solvent of the filtrate was evaporated. The residue obtainedwas purified by chromatography on silica gel using hexane-EtOAc mixturesof increasing polarity as eluent, to afford 71 mg of the title compoundin solid form (yield: 47%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.10 (broad s, NH₂+H₂O) 3.62 (s, 2H),6.80 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.93 (t, J=8.7 Hz, 2H), 7.03(t, J=8.6 Hz, 2H), 7.11 (m, 2H), 7.25 (m, 2H), 8.30 (dd, J_(o)=1.5 Hz,J=4.5 Hz, 2H).

EXAMPLE 694,6-Bis(4-fluoro-3-nitrophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

To a solution of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20g, 0.5 mmol, obtained in example 1) in conc. H₂SO₄ (3 mL), 65% HNO₃ (0.1mL, 0.2 mmol) was added under argon atmosphere. This was heated to 90°C. for 30 min. It was cooled with an ice bath and adjusted to pH=8 with1 N NaOH. It was extracted with EtOAc. The organic phase was dried overNa₂SO₄ and concentrated to dryness. The crude product was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 69 mg of the title compound in solid form(yield: 28%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.28 (s, NH+CD₃OD), 7.03 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.22 (dd, J_(o)=2.7 Hz, J_(m)=10.5 Hz,1H), 7.36 (dd, J_(o)=2.6 Hz, J_(m)=10.4 Hz, 1H), 7.53 (m, 2H), 7.99-8.01(complex signal, 2H), 8.13 (m, 1H), 8.41 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 703-Amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in reference example 15section c, but using6-chloro-2-(4-fluorophenyl)-3,4′-bipyridine-5-carbonitrile (obtained inreference example 12) instead of3-(1-benzylpiperidin-4-yl)-3-oxopropiononitrile, the title compound wasobtained (yield: 41%).

¹H NMR (300 MHz, CD₃OD) δ (TMS): 4.38 (s, NH₂+CD₃OD), 7.05 (t, J=8.8 Hz,2H), 7.26 (dd, J_(o)=1.6 Hz, J_(m)=4.6 Hz, 2H), 7.39 (m, 2H), 8.27 (s,1H), 8.42 (dd, J_(o)=1.4 Hz, J_(m)=4.6 Hz, 2H).

EXAMPLE 713-Amino-6-(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in reference example 15section c, but using6-chloro-2-(4-fluorophenyl)-3,4′-bipyridine-5-carbonitrile (obtained inreference example 12) instead of3-(1-benzylpiperidin-4-yl)-3-oxopropiononitrile and methylhydrazineinstead of hydrazine monohydrate, the title compound was obtained(yield: 70%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.00 (s, 3H), 4.17 (broad s, 2H), 6.98(t, J=8.7 Hz, 2H), 7.09 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.37 (m,2H), 7.90 (s, 1H), 8.50 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 724-[6-(4-Fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]phenol

To a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (0.30 g, 1.4mmol, obtained in reference example 1) in 2-methoxyethanol (2 mL),3-amino-2H-pyrazole (0.13 g, 1.5 mmol), 4-hydroxybenzaldehyde (0.17 g,1.4 mmol), 2-methoxyethanol (2 mL) and 37% HCl (0.04 g, 0.4 mmol) wereadded under argon atmosphere. The mixture was heated to refluxovernight. It was allowed to cool and concentrated. The solid obtainedwas dissolved in CHCl₃ and some drops of MeOH. Saturated NaHCO₃ wasadded and the aqueous phase was extracted 3 times with CHCl₃. Thecombined organic phases were dried over Na₂SO₄ and concentrated todryness. The crude product was purified by chromatography on silica gelusing hexane-EtOAc mixtures of increasing polarity as eluent, to afford0.22 g of the desired compound (yield: 41%).

LC-MS (método 1): t_(R)=5.56 min; m/z=383.0 [M+H]⁺.

EXAMPLE 732-(2,2-Diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 741-(2,2-Diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

In a volumetric flask4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20g, 0.5 mmol, obtained in example 1), KOH (0.03 g, 0.5 mmol),2-bromo-1,1-diethoxyethane (0.10 g, 0.5 mmol) and1-methoxy-2-(2-methoxyethoxy)ethane (2 mL) were introduced under argonatmosphere. The mixture was heated to 100° C. and stirred at thistemperature overnight. It was allowed to cool and a mixture of H₂O-EtOAcwas added. The phases were separated and the aqueous phase was extractedwith EtOAc. The combined organic phases were dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 139 mg of2-(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(yield: 53%) and 60 mg of1-(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4pyridyl)pyrazolo[3,4-b]pyridine (yield: 24%).

Example 73: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.15 (t, J=7.0 Hz, 6H),3.50 (m, 2H), 3.73 (m, 2H), 4.49 (d, J=5.4 Hz, 2H), 5.06 (t, J=5.4 Hz,1H), 6.83 (dd, J_(o)=1.4 Hz, J_(m)=4.4 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H),7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.32(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 74: ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.21 (t, J=6.9 Hz, 6H),3.58 (m, 2H), 3.82 (m, 2H), 4.74 (d, J=5.7 Hz, 2H), 5.19 (t, J=5.7 Hz,1H), 6.81 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.92 (t, J=8.7 Hz, 2H),7.01 (t, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.25 (m, 2H), 7.87 (s, 1H), 8.32(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 754,6-Bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine-3-carbonitrile

Following a similar procedure to that described in example 65, but using3-bromo-4,6-bis(4-fluorophenyl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 66) instead of3-bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 48%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.32 (s, 3H), 6.81 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 6.96 (t, J=8.4 Hz, 2H), 7.05 (t, J=8.4 Hz, 2H), 7.13(m, 2H), 7.29 (m, 2H), 8.35 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 763-Bromo-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

To a solution of3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.20 g, 0.7 mmol, obtained in example 70) in 48% HBr (1 mL) at 0° C., asolution of NaNO₂ (0.05 g, 0.7 mmol) in water (0.1 mL) was addeddropwise over a period of 15 minutes maintaining the temperature at 0-5°C. The mixture was stirred for 15 min at this temperature. Then, asolution of CuBr (0.24 g, 1.7 mmol) in 48% HBr (1 mL) was added slowlyat 0° C. The resulting solution was stirred for 3 h at 0° C. It wasallowed to reach room temperature, neutralized at pH 7 with saturatedsodium bicarbonate and a 30% aqueous NH₃. It was filtered and the solidwas washed with a mixture of CH₂Cl₂ and water. The organic phase waswashed with 1 N NaOH and the aqueous phase extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄ and concentrated todryness. The crude product obtained was purified by chromatography onsilica gel using CHCl₃-MeOH mixtures of increasing polarity as eluent,to afford 50 mg of the title compound (yield: 21%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.24 (s, NH+CD₃OD), 6.92 (m, 2H),7.15 (m, 2H), 7.29 (m, 2H), 7.95 (s, 1H), 8.39 (d, J=6.0 Hz, 2H).

EXAMPLE 77 6-Fluorophenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

3-Amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.20 g, 0.7 mmol, obtained in example 70) and a solution of H₃PO₂ (0.2mL, 2.0 mmol) in water (2 mL) were mixed and allowed to cool to 5° C. Asolution of NaNO₂ (0.10 g, 1.4 mmol) in water (0.4 mL) was addeddropwise. This was stirred for 30 min at 5° C., allowed to reach roomtemperature and stirred at room temperature for 4 h. It was neutralizedwith 1 N NaOH and extracted with CHCl₃. The combined organic phases weredried over Na₂SO₄ and concentrated to dryness. The crude productobtained was purified by chromatography on silica gel using increasingpolarity hexane-EtOAc mixtures as eluent, to afford 63 mg of the titlecompound (yield: 33%).

¹H NMR (300 MHz, MeOH+CDCl₃) δ (TMS): 3.46 (s, NH+CD₃OD), 6.92 (t, J=8.6Hz, 2H), 7.07 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 7.26 (m, 2H), 8.08(s, 1H), 8.09 (s, 1H), 8.37 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 78N-Methyl-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]amine

To a solution of2-(3-chloropropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.07 g, 0.1 mmol, obtained in example 16) in acetonitrile (0.3 mL),methylamine (1.8 mL of a 33% solution in EtOH, 14.6 mmol) was addedunder argon atmosphere. This was heated to 60° C. for 3 days, addingmethylamine (0.9 mL and 3.6 mL of a 33% solution in EtOH) after 24 and48 h respectively. The organic phase was dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bysilica gel EtOAc-MeOH mixtures of using increasing polarity as eluent,to afford 24 mg of the title compound in solid form (yield: 29%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.00 (broad s, NH+H₂O), 2.53 (m, 2H),2.61 (s, 3H), 2.99 (t, J=6.7 Hz, 2H), 4.67 (t, J=6.4 Hz, 2H), 6.82 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.27 (m, 2H), 7.90 (s, 1H), 8.32 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 79[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]methanol

A suspension of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20g, 0.5 mmol, obtained in example 1) in 30-40% aqueous formaldehyde (0.9mL) was stirred at 130° C. under argon atmosphere for 4 h. The solventwas concentrated and the residue was dissolved in a mixture of CHCl₃ andwater and the phases were separated. The organic phase was dried overNa₂SO₄ and concentrated to dryness. The crude product obtained waspurified on chromatography on silica gel using hexane-EtOAc mixtures ofincreasing polarity as eluent, to afford 140 mg of the title compound insolid form (yield: 65%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.5 (t, 1H, OH), 6.11 (d, J=7.8 Hz,2H), 6.85 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H), 6.97 (t, J=8.7 Hz, 1H),7.08 (t, J=8.7 Hz, 1H), 7.16 (m, 2H), 7.31 (m, 2H), 7.97 (s, 1H), 8.37(dd, J_(o)=1.6 Hz, J_(m)=4.3 Hz, 2H).

EXAMPLE 802-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-N,N-dimethylacetamideEXAMPLE 812-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-N,N-dimethylacetamide

Following a similar procedure to that described in examples 73 and 74,but using 2-chloro-N,N-dimethylacetamide instead of2-bromo-1,1′-diethoxyethane, the title compounds were obtained.

Example 80: yield: 10%

Example 81: yield 32%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.01 (s, 3H),3.18 (s, 3H), 5.47 (s, 2H), 6.79 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H),6.91 (t, J=8.7 Hz, 1H), 7.01 (t, J=8.6 Hz, 1H), 7.15 (m, 2H), 7.23 (m,2H), 7.95 (s, 1H), 8.31 (dd, J_(o)=1.6 Hz, J_(m)=4.3 Hz, 2H).

EXAMPLE 824,6-Bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 834,6-Bis(4-fluorophenyl)-1-[2-(2-methoxyethoxy)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 1-bromo-2-(2-methoxyethoxy)ethane instead of iodoethane, the titlecompounds were obtained.

Example 82: yield: 27%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.28 (s, 3H),3.45 (m, 2H), 3.57 (m, 2H), 4.05 (t, J=5.1 Hz, 2H), 4.63 (t, J=5.1 Hz,2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H),6.99 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.93 (s, 1H), 8.31(dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 83: yield: 19%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.32 (s, 3H),3.50 (m, 2H), 3.68 (m, 2H), 4.08 (t, J=6.0 Hz, 2H), 4.81 (t, J=6.0 Hz,2H), 6.81 (dd, J_(o)=1.4 Hz, J_(m)=4.4 Hz, 2H), 6.92 (t, J=8.7 Hz, 2H),7.01 (t, J=8.6 Hz, 2H), 7.13 (m, 2H), 7.26 (m, 2H), 7.86 (s, 1H), 8.32(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 844,6-Bis(4-fluorophenyl)-2-[3-(morpholin-4-yl)propyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridinea)3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate

Following a similar procedure to that described in example 12 section b,but using3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-ol(obtained in example 18) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethanol, the desired compoundwas obtained (yield: quantitative).

b) Title Compound

In a volumetric flask,3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate (0.10 g, 0.2 mmol, obtained in section a), NaI (0.003g, 0.02 mmol), morpholine (0.03 g, 0.4 mmol) and 1,2-dimethoxyethane (2mL) were introduced under argon atmosphere. The mixture was heated to90° C. and stirred at this temperature overnight. A mixture of water andEtOAc was added. The phases were separated. The aqueous phase wasextracted with EtOAc. The organic phase was dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using increasing polarity mixtures ofEtOAc-MeOH as eluent, to afford 37 mg of the title compound (yield:36%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.27 (m, 2H), 2.30-2.43 (complexsignal, 6H), 3.69 (m, 4H), 4.53 (t, J=6.6 Hz, 2H), 6.83 (dd, J_(o)=1.6Hz, J_(m)=4.4 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H),7.14 (m, 2H), 7.31 (m, 2H), 7.81 (s, 1H), 8.32 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H).

EXAMPLE 854,6-Bis(6-chloropyridin-3-yl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 864,6-Bis(6-chloropyridin-3-yl)-1-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 73 and 74,but using4,6-bis(6-chloropyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 40) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine andiodomethane instead of 2-bromo-1,1-diethoxyethane, the title compoundswere obtained.

Example 85: yield: 26%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (s,NH+H₂O), 4.32 (s, 3H), 6.88 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.19(d, J=8.4 Hz, 1H), 7.31 (m, 2H), 7.58 (dd, J_(o)=2.4 Hz, J_(m)=8.4 Hz,1H), 7.84 (s, 1H), 8.37 (dd, J_(o)=2.4 Hz, J_(m)=6.9 Hz, 2H), 8.43 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 86: yield: 27%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (s,NH+H₂O), 4.26 (s, 3H), 6.88 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H), 7.20(d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.35 (dd, J_(o)=2.4 Hz,J_(m)=8.1 Hz, 1H), 7.50 (dd, J_(o)=2.6 Hz, J_(m)=8.2 Hz, 1H), 7.91 (s,1H), 8.34 (d, J=2.1 Hz, 1H), 8.43-8.45 (complex signal, 3H)

EXAMPLE 874,6-Bis(6-chloropyridin-3-yl)-3-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method A,but using 1-(6-chloropyridin-3-yl)-2-(4-pyridyl)ethanone (obtained inexample reference 9) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanoneand 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole, thetitle compound was obtained (yield: 9%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 2.09 (s, 3H), 3.51 (s, NH+H₂O),6.92 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 1H), 7.54(dd, J_(o)=2.4 Hz, J_(m)=8.4 Hz, 1H), 8.26 (broad s, 1H), 8.35-8.38(complex signal, 3H).

EXAMPLE 884,6-Bis(6-methylpyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method A,but using 1-(6-methylpyridin-3-yl)-2-(4-pyridyl)ethanone (obtained inreference example 13) instead of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone, the title compound wasobtained (yield: 23%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.59 (s, NH+H₂O), 2.59 (s, 6H), 6.90(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.09 (d,J=7.8 Hz, 1H), 7.33 (m, 2H), 7.99 (s, 1H), 8.39 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 8.47 (d, J=2.1 Hz, 1H), 8.80 (broad s, 1H).

EXAMPLE 894,6-Bis(4-fluorophenyl)-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing N-(2-bromoethyl)phthalimide instead of iodomethane, the titlecompound was obtained (yield: 29%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.32 (t, J=6.1 Hz, 2H), 4.76 (t, J=6.0Hz, 2H), 6.81 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.88 (t, J=8.7 Hz,2H), 6.95 (t, J=8.6 Hz, 2H), 7.07 (m, 2H), 7.25 (m, 2H), 7.50 (m, 2H),7.61 (s, 1H), 7.71 (m, 2H), 8.32 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 902-(2-Aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

To a solution of4,6-bis(4-fluorophenyl)-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.09 g, 0.2 mmol, obtained in example 89) in EtOH (2 mL), hydrazinemonohydrate (0.02 g, 0.3 mmol) was added and the mixture was heated toreflux for 3 h. A mixture of water and EtOAc was added. The phases wereseparated. The aqueous phase was extracted with EtOAc. The organic phasewas dried over Na₂SO₄ and concentrated to dryness. The crude productobtained was purified by chromatography on silica gel using CHCl₃-MeOHmixtures of increasing polarity as eluent, to afford 57 mg of the titlecompound (yield: 83%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (s, NH₂+H₂O), 3.38 (t, J=5.7 Hz,2H), 4.49 (t, J=5.5 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H),6.90 (t, J=8.8 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.15 (m, 2H), 7.31 (m,2H), 7.85 (s, 1H), 8.32 (dd, J_(o)=1.6 Hz, J_(m)=4.6 Hz, 2H).

EXAMPLE 912-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethanol

A solution of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrazolo[3,4-b]pyridine(1.08 g, 2.09 mmol, obtained in example 24) in a 4:2:1 mixture ofAcOH:THF:H₂O (42 mL) was heated to 55° C. overnight. The mixture wasallowed to cool and basified with saturated NaHCO₃ and extracted withEtOAc. The organic phase was dried over Na₂SO₄ and concentrated todryness. The crude product obtained was purified by chromatography onsilica gel using hexane-EtOAc mixtures of increasing polarity as eluent,to afford 0.78 g of the title compound (yield: 87%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61 (broad s, OH+H₂O), 4.21 (t, J=4.7Hz, 2H), 4.58 (t, J=4.7 Hz, 2H), 6.83 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz,2H), 6.91 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.27(m, 2H), 7.87 (s, 1H), 8.33 (dd, J_(o)=1.6 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 926-(4-Fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtainedin example 77) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine andiodomethane instead of iodoethane, the title compound was obtained(yield: 35%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (broad s, NH+H₂O), 4.31 (s, 3H),6.95 (t, J=8.7 Hz, 2H), 7.11 (d, J=6.0 Hz, 2H), 7.41 (m, 2H), 8.01 (s,1H), 8.06 (s, 1H), 8.51 (d, J=6.0 Hz, 2H).

EXAMPLE 934,6-Bis(4-fluorophenyl)-2-(3-phthalimidopropyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing N-(3-bromopropyl)phthalimide instead of iodoethane, the titlecompound was obtained (yield: 31%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.54 (q, J=6.4 Hz, 2H), 3.79 (t, J=6.2Hz, 2H), 4.50 (t, J=6.6 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz,2H), 6.89 (t, J=8.7 Hz, 2H), 7.02 (t, J=8.7 Hz, 2H), 7.17 (m, 2H), 7.28(m, 2H), 7.71 (m, 2H), 7.83 (m, 2H), 7.93 (s, 1H), 8.32 (dd, J_(o)=1.6Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 942-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetaldehyde

In a volumetric flask,2-(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.31 g, 0.6 mmol, obtained in example 73) and 1 N HCl (2.6 mL) wereintroduced. The mixture was heated to 100° C. for 1 hour. It was allowedto cool, adjusted to pH=7 and extracted with EtOAc. The organic phasewas dried over Na₂SO₄ and concentrated to dryness. The crude productobtained was purified by chromatography on silica gel using hexane-EtOAcmixtures of increasing polarity eluent, to afford 166 mg of the titlecompound (yield: 65%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.26 (s, 2H), 6.83 (dd, J_(o)=1.4 Hz,J_(m)=4.4 Hz, 2H), 6.91 (t, J=8.5 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 7.15(m, 2H), 7.30 (m, 2H), 7.88 (s, 1H), 8.31 (m, 2H), 9.85 (s, 1H).

EXAMPLE 952-(3-Aminopropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 90, but using4,6-bis(4-fluorophenyl)-2-(3-phthalimidopropyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 93) instead of4,6-bis(4-fluorophenyl)-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 49%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.54 (s, NH₂+H₂O), 2.19 (m, 2H), 2.76(t, J=6.7 Hz, 2H), 4.57 (t, J=6.7 Hz, 2H), 6.83 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.13(m, 2H), 7.30 (m, 2H), 7.81 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 96N-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxamide

Following a similar procedure to that described in example 48, but using1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid instead of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]aceticacid and3-aminomethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 68) instead of morpholine, the title compound wasobtained (yield: 26%).

EXAMPLE 97N-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl]piperidine-4-carboxamide

Following a similar procedure to that described in example 36, but usingN-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxamide(obtained in example 96) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 63%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.40-1.90 (complex signal, 3H+ H₂O),2.18 (m, 2H), 2.63 (m, 2H), 3.13 (m, 2H), 4.15 (d, J=5.1 Hz, 2H), 5.20(broad s, 1H, NH), 6.20 (broad s, 1H, NH), 6.78 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 6.94 (t, J=8.7 Hz, 2H), 7.03 (t, J=8.7 Hz, 2H),7.08-7.14 (complex signal, 4H), 8.30 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz,2H).

EXAMPLE 982-(3-Benzyloxypropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 991-(3-Benzyloxypropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 3-bromopropanol benzylic ether instead of Iodoethane, the titlecompounds were obtained.

Example 98: yield: 43%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.38 (m, 2H),3.48 (t, J=5.6 Hz, 2H), 4.44 (s, 2H), 4.57 (t, J=6.7 Hz, 2H), 6.82 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.10 (m, 2H), 7.26-7.32 (complex signal, 7H), 7.73 (s, 1H),8.32 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H).

Example 99: yield: 20%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.19 (m, 2H),3.58 (t, J=6.1 Hz, 2H), 4.48 (s, 2H), 4.75 (t, J=6.9 Hz, 2H), 6.81 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.12 (m, 2H), 7.24-7.33 (complex signal, 7H), 7.86 (s, 1H),8.32 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 100N,N-Diethyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amineEXAMPLE 101N,N-Diethyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]ethyl]amine

Following a similar procedure to that described in examples 6 and 7, butusing N-(2-chloroethyl)diethylamine hydrochloride instead of iodoethaneand 2 equivalents of KOH, the title compounds were obtained.

Example 100: yield: 5%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 0.99 (t, J=7.2Hz, 6H), 2.56 (c, J=7.1 Hz, 4H), 3.08 (t, J=6.5 Hz, 2H), 4.48 (t, J=6.5Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.8 Hz,2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H),8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 101: yield: 73%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.05 (t, J=7.2Hz, 6H), 2.66 (c, J=7.2 Hz, 4H), 3.09 (t, J=7.2 Hz, 2H), 4.69 (t, J=7.2Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.92 (t, J=8.7 Hz,2H), 6.98 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.26 (m, 2H), 7.85 (s, 1H),8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1024,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-2-(3-pyridylmethyl)pyrazolo[3,4-b]pyridineEXAMPLE 1034,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1-(3-pyridylmethyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 3-chloromethylpyridine hydrochloride instead of iodoethane, thetitle compounds were obtained.

Example 102: yield: 16%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.63 (s, 2H),6.81 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.8 Hz, 2H), 6.99(t, J=8.7 Hz, 2H), 7.10 (m, 2H), 7.31 (m, 2H), 7.82 (m, 2H), 8.32 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 8.61 (dd, J_(o)=1.5 Hz, J_(m)=4.8 Hz,2H), 8.68 (s, 1H).

Example 103: yield: 22%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.80 (s, 2H),6.81 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.94 (t, J=8.6 Hz, 2H), 7.01(t, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.27 (m, 2H), 7.79 (m, 1H), 7.88 (s,1H), 8.32 (dd, J_(o)=1.4 Hz, J_(m)=4.4 Hz, 2H), 8.56 (d, J=5.0 Hz, 2H),8.75 (s, 1H).

EXAMPLE 104N,N-Dimethyl-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]amineEXAMPLE 105N,N-Dimethyl-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propyl]amine

Following a similar procedure to that described in examples 6 and 7, butusing N-(3-chloropropyl)dimethylamine hydrochloride instead ofiodoethane, the title compounds were obtained.

Example 104: 22%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.21-2.29 (complexsignal, 10H), 4.51 (t, J=6.6 Hz, 2H), 6.82 (dd, J_(o)=1.6 Hz, J_(m)=4.4Hz, 2H), 6.89 (t, J=8.8 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H),7.30 (m, 2H), 7.81 (s, 1H), 8.31 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 105: yield: 19%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.18-2.27(complex signal, 8H), 2.43 (t, J=7.2 Hz, 2H), 4.65 (t, J=7.1 Hz, 2H),6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.93 (t, J=8.8 Hz, 2H), 7.01(t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.27 (m, 2H), 7.86 (s, 1H), 8.32 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1061-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-ol

In a volumetric flask,2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetaldehyde(0.08 g, 0.2 mmol, obtained in example 94), sodium triacetoxyborohydride(0.08 g, 0.4 mmol), 4-hydroxypiperidine (0.02 g, 0.2 mmol) and1,2-dichloroethane (3 mL) were introduced under argon atmosphere. Themixture was stirred overnight at room temperature. It was concentratedand a mixture of water and EtOAc were added. The phases were separated.The aqueous phase was extracted with EtOAc. The organic phase was driedover Na₂SO₄ and concentrated to dryness. The crude product obtained waspurified by chromatography on silica gel using increasing polaritymixtures of EtOAc-MeOH as eluent, to afford 19 mg of the title compound(yield: 20%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (broad s 1H+OH+H₂O), 1.85 (m, 2H),2.05 (m, 2H), 2.30 (m, 2H), 2.80 (m, 2H), 3.01 (m, 2H), 4.54 (m, 2H),6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.6 Hz, 2H), 7.01(t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.34 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 1073-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-2-hydroxypropan-1-olEXAMPLE 1083-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-2-hydroxypropan-1-ol

Following a similar procedure to that described in examples 6 and 7, butusing 3-bromopropane-1,2-diol instead of iodoethane, the title compoundswere obtained.

Example 107: yield: 17%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.49 (s, 1H,OH), 3.72 (m, 2H), 4.32 (m, 1H), 4.60 (m, 2H), 5.30 (s, 1H, OH), 6.83(dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.91 (t, J=8.7 Hz, 2H), 7.01 (t,J=8.6 Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.88 (s, 1H), 8.32 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

Example 108: yield: 26%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 3.65 (m, 2H),4.26 (m, 1H), 4.78 (m, 2H), 5.30 (s, 2H, OH), 6.82 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 6.94 (t, J=8.6 Hz, 2H), 7.03 (t, J=8.7 Hz, 2H), 7.14(m, 2H), 7.28 (m, 2H), 7.91 (s, 1H), 8.34 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 1094,6-Bis(4-fluorophenyl)-S-(4-pyridyl)-2-(4-pyridylmethyl)pyrazolo[3,4-b]pyridineEXAMPLE 1104,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-1-(4-pyridylmethyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 4-chloromethylpyridine hydrochloride instead of iodoethane, thetitle compounds were obtained.

Example 109: yield: 29%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.63 (s, 2H),6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.99(t, J=8.7 Hz, 2H), 7.12 (m, 2H), 7.23-7.33 (complex signal, 4H), 7.84(s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 8.61 (dd, J_(o)=1.5Hz, J_(m)=4.8 Hz, 2H).

Example 110: yield: 15%; 5.80 (s, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H), 6.93 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H),7.20-7.26 (complex signal, 4H), 7.93 (s, 1H), 8.34 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 8.61 (dd, J_(o)=1.5 Hz, J_(m)=4.8 Hz, 2H).

EXAMPLE 111N-(tert-Butoxycarbonyl)-[1-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]piperidin-4-yl]amine

To a solution of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate (0.15 g, 0.3 mmol, obtained in example 84 section a) inacetonitrile (2 mL), N-(tert-butoxycarbonyl)-N-(4-piperidyl)amine (0.12g, 0.6 mmol) was added under argon atmosphere and heated to 60° C.overnight. A mixture of CHCl₃ and saturated NaHCO₃ were added. Thephases were separated. The aqueous phase was extracted with CHCl₃. Theorganic phase was dried over Na₂SO₄ and concentrated to dryness. Thecrude product obtained was purified by chromatography on silica gelusing increasing polarity mixtures of EtOAc-MeOH as eluent, to afford 40mg of the title compound (yield: 22%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.44 (broad s, 2H+NH₂+H₂O), 1.95 (m,2H), 2.06 (m, 2H), 2.25 (m, 2H), 2.35 (m, 2H), 3.46 (m, 2H), 4.40 (m,1H), 4.51 (t, 2H), 6.83 (d, J=6.0 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00(t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.80 (s, 1H), 8.32 (d,J=6.0 Hz, 2H).

EXAMPLE 1122-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 1131-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtainedin example 77) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate (obtained inexample 14 section a) instead of iodoethane, the title compounds wereobtained,

Example 112: yield: 26%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.50 (s, 9H),2.17-2.32 (complex signal, 2H), 2.99 (m, 2H), 4.33 (m, 2H), 4.60 (m,1H), 6.95 (t, J=8.7 Hz, 2H), 7.11 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H),7.41 (m, 2H), 8.06 (s, 1H), 8.07 (s, 1H), 8.52 (dd, J_(o)=1.6 Hz,J_(m)=4.4 Hz, 2H).

Example 113: yield: 55%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.50 (s, 9H),2.04 (m, 2H), 2.30 (m, 2H), 3.00 (m, 2H), 4.42 (m, 2H), 5.10 (m, 1H),7.00 (t, J=8.6 Hz, 2H), 7.10 (dd, J_(o)=1.6 Hz, J_(m)=4.5 Hz, 2H), 7.37(m, 2H), 8.07 (s, 1H), 8.10 (s, 1H), 8.52 (dd, J_(o)=1.8 Hz, J_(m)=4.5Hz, 2H).

EXAMPLE 1143-Methyl-4,6-bis(6-methylpyridin-3-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method A,but using 1-(6-methylpyridin-3-yl)-2-(4-pyridyl)ethanone (obtained inreference example 13) instead of1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole, the titlecompound was obtained (yield: 24%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.07 (s, 3H), 2.54 (s, 3H), 2.57 (s,3H), 6.85 (m, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.30(m, 1H), 8.10 (dd, J_(o)=2.4 Hz, J_(m)=8.1 Hz, 1H), 8.32 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H), 8.38 (s, 1H), 8.57 (s, 1H), 10.74 (broad s, NH).

EXAMPLE 1151-[3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]piperidin-4-one

In a volumetric flask,3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate (0.15 g, 0.3 mmol, obtained in example 84 section a),NaI (0.008 g, 0.06 mmol), 4-piperidone monohydrate hydrochloride (0.04g, 0.3 mmol), K₂CO₃ (0.07 g, 0.5 mmol) and DMF (2 mL) were introducedunder argon atmosphere. The mixture was heated to 60° C. for 24 h. Itwas allowed to cool and a mixture of water and EtOAc was added. Thephases were separated. The aqueous phase was extracted with EtOAc. Theorganic phase was dried over Na₂SO₄ and concentrated to dryness. Thecrude product obtained was purified by chromatography on silica gelusing EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 16mg of the title compound (yield: 10%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (broad s, 4H+ H₂O), 2.30 (m, 2H),2.42 (m, 2H), 2.48 (m, 2H), 2.73 (t, 2H), 4.55 (t, 2H), 6.83 (d, J=6.0Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.18 (m, 2H),7.27 (m, 2H), 7.82 (s, 1H), 8.32 (d, J=6.0 Hz, 2H).

EXAMPLE 116N-(tert-Butoxycarbonyl)-[1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-]pyridin-2-yl]ethyl]piperidin-4-yl]aminea)2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate

Following a similar procedure to that described in example 12 section b,but using2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethanol(obtained in example 91) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethanol, the desired compoundwas obtained (yield: quantitative).

b) Title Compound

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate the desired compound was obtained (yield: 66%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.44 (s, 9H), 1.57 (broad s,1H+NH+H₂O), 1.90 (m, 2H), 2.22 (m, 2H), 2.82 (m, 2H), 3.01 (t, J=6.6 Hz,2H), 3.45 (m, 1H), 4.40 (m, 1H), 4.52 (t, J=6.5 Hz, 2H), 6.82 (d, J=5.7Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 7.14 (m, 2H),7.29 (m, 2H), 7.82 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 117N-Methyl-[1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-yl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and N-methyl-N-(piperidin-4-yl)amine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 50%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61 (broad s, 1H+NH+H₂O), 2.28 (s,3H), 2.41 (m, 4H), 2.57 (m, 4H), 3.03 (t, J=6.5 Hz, 2H), 4.55 (t, J=6.5Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz,2H), 7.01 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H),8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 118[1-[3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]piperidin-4-yl]amine

Following a similar procedure to that described in example 36, but usingN-(tert-butoxycarbonyl)-[1-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]piperidin-4-yl]amine(obtained in example 111) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 89%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.35 (m, 2H), 1.62 (broad s NH₂+H₂O),1.85 (m, 2H), 2.03 (m, 2H), 2.25 (m, 2H), 2.36 (m, 2H), 2.70 (m, 1H),2.82 (m, 2H), 4.52 (d, J=6.6 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.13 (m, 2H),7.29 (m, 2H), 7.81 (s, 1H), 8.31 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 1192-[1-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-yl]ethanol

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 2-(4-piperidyl)ethanol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 50%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.48-1.53 (complex signal, 5H), 2.11(m, 2H), 2.88 (m, 2H), 2.99 (m, 2H), 3.70 (t, J=6.5 Hz, 2H), 4.55 (t,J=6.5 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.86 (s,1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 120[1-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-yl]amine

Following a similar procedure to that described in example 36, but usingN-(tert-butoxycarbonyl)-[1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-yl]amine(obtained in example 116) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 77%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.38 (m, 2H), 1.78 (broad s,2H+NH₂+H₂O), 2.18 (m, 2H), 2.75 (m, 1H), 2.84 (m, 2H), 3.02 (t, J=6.3Hz, 2H), 4.54 (t, J=6.5 Hz, 2H), 6.82 (d, J=5.7 Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.84 (s,1H), 8.31 (d, J=6.0 Hz, 2H).

EXAMPLE 1216-(4-Fluorophenyl)-2-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 112) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 77%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.89 (m, NH+H₂O), 2.25 (m, 2H), 2.30(m, 2H), 2.89 (m, 2H), 3.34 (m, 2H), 4.60 (m, 1H), 6.95 (t, J=8.7 Hz,2H), 7.11 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.40 (m, 2H), 8.07 (s,1H), 8.08 (s, 1H), 8.51 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 1226-(4-Fluorophenyl)-1-(4-piperidyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 113) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: quantitative).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.60 (m, NH+H₂O), 2.42 (m, 2H), 2.67(m, 2H), 3.28 (m, 2H), 3.72 (m, 2H), 5.28 (m, 1H), 7.00 (t, J=8.7 Hz,2H), 7.11 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.37 (m, 2H), 8.10 (s,1H), 8.12 (s, 1H), 8.54 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 1233-Amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in reference example 15section c, but using2-chloro-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]pyridine-3-carbonitrile(obtained in reference example 14) instead of3-(1-benzylpiperidin-4-yl)-3-oxopropiononitrile, the title compound wasobtained (yield: 78%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.44 (s, 3H), 4.32 (broad s, NH₂), 6.61(d, J=5.1 Hz, 1H), 7.44-7.84 (complex signal, 2H), 7.65 (d, J=7.2 Hz,1H), 7.84 (s, 1H), 8.30 (d, J=5.1 Hz, 1H), 8.40 (s, 1H), 9.55 (broad s,NH).

EXAMPLE 1244,6-Bis(4-fluorophenyl)-2-[3-[1-(tert-butoxycarbonyl)piperazin-4-yl]propyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 84 section b,but using 1-(tert-butoxycarbonyl)piperazine instead of morpholine andadding triethylamine (1.5 equivalents), the desired compound wasobtained (yield: 14%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.66 (m, 2H), 2.98 (m, 4H), 3.10 (m,2H), 3.66-3.74 (complex signal, 4H), 4.66 (m, 2H), 6.85 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H), 6.91 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H),7.14 (m, 2H), 7.28 (m, 2H), 7.98 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

EXAMPLE 1254,6-Bis(4-fluorophenyl)-2-[3-(piperazin-1-yl)propyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using4,6-bis(4-fluorophenyl)-2-[3-[1-(tert-butoxycarbonyl)piperazin-4-yl]propyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 124) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: quantitative).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.78 (broad s, 2H+NH+H₂O), 2.26 (m,2H), 2.40-2.59 (complex signal, 6H), 3.04 (m, 2H), 4.52 (m, 2H), 6.83(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t,J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.80 (s, 1H), 8.31 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1265-[2-(Methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 77, but using3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(obtained in example 123) instead of3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine, thetitle compound was obtained (yield: 34%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.55 (broad s, NH+H₂O), 6.70 (d, J=5.1Hz, 1H), 7.50 (m, 2H), 7.72 (m, 1H), 7.86 (s, 1H), 8.24 (s, 1H), 8.35(d, J=5.1 Hz, 1H), 8.54 (s, 1H).

EXAMPLE 1275-[2-(Methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 56, but using5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(obtained in example 126) instead of4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineand 2 equivalents of m-chloroperbenzoic acid, the title compound wasobtained (yield: quantitative).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (broad s, NH+H₂O), 3.22 (8, 3H),7.21 (d, J=5.1 Hz, 1H), 7.49 (d, J=4.8 Hz, 2H), 7.71 (m, 1H), 7.84 (s,1H), 8.30 (s, 1H), 8.71 (m, 2H).

EXAMPLE 128(1S)-N-(1-Phenylethyl)-[4-[6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2-yl]amine

A mixture of5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(0.55 g, 0.13 mmol, obtained in example 127) and (1S)-1-phenylethylamine(0.16 g, 1.3 mmol) was heated to 100° C. for 1 h. It was allowed to cooland the crude product obtained was purified by chromatography on silicagel using increasing polarity mixtures of EtOAc-hexane as eluent, toafford 10 mg of the title compound (yield: 16%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 1.50 (d, 3H), 3.80 (broad s, 2NH+H₂O), 6.30 (d, 1H), 7.20-7.40 (complex signal, 6H), 7.50 (d, 1H),7.68 (d, 1H), 7.76 (d, 1H), 7.83 (s, 1H), 8.08 (d, 1H), 8.15 (s, 1H),8.24 (broad s, 1H).

EXAMPLE 1291-[3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]piperidin-4-ol

Following a similar procedure to that described in example 111, butusing piperidin-4-ol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 39%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (m, 2H), 1.88-2.50 (complexsignal, 5H+OH+H₂O), 2.75 (m, 2H), 3.44-3.51 (complex signal, 4H), 4.52(t, J=6.6 Hz, 2H), 6.83 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.89 (t,J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.34 (m, 2H), 7.82(s, 1H), 8.32 (dd, J=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1302-[1-[3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]piperidin-4-yl]ethanol

Following a similar procedure to that described in example 111, butusing 2-(4-piperidyl)ethanol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 44%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.20-2.00 (broad s, 8H+OH+H₂O), 2.50(m, 1H), 2.85 (m, 1H), 3.50 (m, 1H), 3.70 (m, 4H), 4.59 (m, 2H), 6.83(d, J=6.0 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14(m, 2H), 7.30 (m, 2H), 7.89 (s, 1H), 8.32 (d, J=6.0 Hz, 2H).

EXAMPLE 1314,6-Bis(4-fluorophenyl)-3-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridinea)3-(1-Benzylpiperidin-4-yl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 1 method A,but using 3-amino-5-(1-benzylpiperidin-4-yl)-2H-pyrazole (obtained inreference example 15) instead of 3-amino-2H-pyrazole, the title compoundwas obtained (yield: 6%).

b) Title Compound

To a solution of3-(1-benzylpiperidin-4-yl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(23 mg, 0.04 mmol, obtained in the previous section) in MeOH (1 mL),Pd/C and a solution of HCOONH₄ (0.01 g, 0.2 mmol) in water (0.06 mL)were added under argon atmosphere. The mixture was heated to reflux for5 h. It was filtered through celite and concentrated. The residue wasdissolved in CHCl₃ and washed with saturated NaHCO₃, to afford 2 mg ofthe title compound (yield: 10%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.10-1.90 (broad s, 7H), 2.23 (m, 2H),2.99 (m, 2H), 6.80 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.02 (t, J=8.7 Hz, 2H), 7.12 (m, 2H), 7.28 (m, 2H), 8.28 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1326-(4-Fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

Following a similar procedure to that described in example 65, but using3-bromo-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 76) instead of3-bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 38%).

EXAMPLE 1332-[2-[[1-(tert-Butoxycarbonyl)piperidin-4-yl]amino]ethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and [N-(tert-butoxycarbonyl)piperidin-4-yl]amineinstead of N-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desiredcompound was obtained (yield: 40%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.20 (m, 2H), 1.45 (s, 9H), 1.55 (broads NH+H₂O), 1.83 (m, 2H), 2.65 (m, 1H), 2.77 (m, 2H), 3.31 (t, 2H), 4.02(m, 2H), 4.53 (t, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90(t, J=8.8 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.28 (m, 2H),7.84 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1344,6-Bis(4-fluorophenyl)-2-[2-[(4-piperidyl)amino]ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using2-[2-[[1-(tert-butoxycarbonyl)piperidin-4-yl]amino]ethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 133) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 97%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.30 (m, 2H), 1.70 (broad s, 2 NH+H₂O),1.85 (m, 2H), 2.61 (m, 3H), 3.09 (m, 2H), 3.31 (t, J=5.7 Hz, 2H), 4.53(t, J=5.7 Hz, 2H), 6.82 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.90 (t,J=8.8 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85(s, 1H), 8.32 (dd, J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H).

EXAMPLE 135N-(2-Methoxyethyl)-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 2-methoxyethylamine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 63%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.57 (broad s, NH+H₂O), 2.81 (t, J=5.1Hz, 2H), 3.30 (t, J=5.8 Hz, 2H), 3.31 (s, 3H), 3.45 (t, J=5.1 Hz, 2H),4.55 (t, J=5.7 Hz, 2H), 6.82 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H), 6.89(t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H),7.85 (s, 1H), 8.32 (dd, J=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1361-[4-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperazin-1-yl]ethanone

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 1-(piperazin-1-yl)ethanone instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 50%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.07 (s, 3H), 2.50 (m, 4H), 3.07 (t,J=6.3 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 3.57 (t, J=4.9 Hz, 2H), 4.55 (t,J=6.3 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.82 (s,1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1373-[4,6-Diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-olEXAMPLE 1383-[4,6-Diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propan-1-ol

Following a similar procedure to that described in examples 6 and 7, butusing 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained inexample 2) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and3-iodopropanol instead of iodoethane, the title compounds were obtained.

Example 137: yield: 44%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (s,OH+H₂O), 2.25 (m, 2H), 3.70 (m, 2H), 4.62 (t, J=6.3 Hz, 2H), 6.83 (dd,J_(o)=1.6 Hz, J_(m)=4.6 Hz, 2H), 7.17-7.34 (complex-signal, 10H), 7.84(s, 1H), 8.26 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 138: yield: 27%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.58 (s,OH+H₂O), 2.15 (m, 2H), 3.59 (m, 2H), 4.79 (t, J=6.0 Hz, 2H), 6.83 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 7.17 (m, 2H), 7.21-7.33 (complexsignal, 8H), 7.91 (s, 1H), 8.27 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 139 2-Ethyl 4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 140 1-Ethyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained inexample 2) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine, thetitle compounds were obtained.

Example 139: yield: 12%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.67 (t, J=7.3Hz, 3H), 4.50 (c, J=7.3 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz,2H), 7.15-7.34 (complex signal, 10H), 7.80 (s, 1H), 8.25 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H).

Example 140: yield: 21%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61 (t, J=7.2Hz, 3H), 4.68 (c, J=7.2 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz,2H), 7.17 (m, 2H), 7.23-7.32 (complex signal, 8H), 7.88 (s, 1H), 8.26(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1414,6-Diphenyl-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained inexample 2) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine andN-(2-bromoethyl)phthalimide instead of iodoethane, the title compoundwas obtained (yield: 31%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.32 (t, J=6.1 Hz, 2H), 4.75 (t, J=6.1Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.11 (m, 2H),7.18-7.32 (complex signal, 7H), 7.73 (m, 2H), 7.80 (s, 1H), 7.83 (m,2H), 8.25 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1422-(2-Aminoethyl)-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 90, but using2-(2-phthalimidoethyl)-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 141) instead of4,6-bis(4-fluorophenyl)-2-(2-phthalimidoethyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 51%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.50 (s, NH₂+H₂O), 3.37 (t, J=5.5 Hz,2H), 4.48 (t, J=5.4 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H),7.17-7.34 (complex signal, 10H), 7.86 (s, 1H), 8.25 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

EXAMPLE 1432-Allyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridineEXAMPLE 1441-Allyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butusing allyl bromide instead of iodoethane, the title compounds wereobtained.

Example 143: yield: 33%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.08 (d, J=6.3Hz, 2H), 5.40 (m, 2H), 6.16 (m, 1H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.13 (m, 2H),7.30 (m, 2H), 7.78 (s, 1H), 8.34 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

Example 144: yield: 10%; ¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.22-5.34(complex signal, 4H), 6.14 (m, 1H), 6.81 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H), 6.93 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 7.14 (m, 2H),7.29 (m, 2H), 7.87 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1451-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-one

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 4-piperidone monohydrate hydrochloride instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine and adding triethylamine (3equivalents), the desired product was obtained (yield: 18%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.41 (t, J=6.0 Hz, 4H), 2.84 (t, J=6.0Hz, 4H), 3.20 (t, J=6.4 Hz, 2H), 4.58 (t, J=6.4 Hz, 2H), 6.83 (d, J=6.0Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H),7.30 (m, 2H), 7.85 (s, 1H), 8.32 (d, J=6.0 Hz, 2H).

EXAMPLE 1463-Aminomethyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 68, but using6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(obtained in example 132) instead of4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile,the title compound was obtained (yield: 22%).

¹H NMR (300 MHz, CDCl₃+CD₃OD) δ (TMS): 4.24 (s, 2H), 4.25 (broad s,NH+NH₂+CD₃OD), 6.95 (m, 2H), 7.16 (m, 2H), 7.29 (m, 2H), 8.25 (broad s,1H), 8.38 (broad s, 2H).

EXAMPLE 1473-Amino-6-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in reference example 15section c, but using6-chloro-2-(4-fluorophenyl)-4-methyl-3,4′-bipyridine-5-carbonitrile(obtained in reference example 18) instead of3-(1-benzylpiperidin-4-yl)-3-oxopropiononitrile, the title compound wasobtained (yield: 27%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (broad s, NH+NH₂+H₂O), 2.51 (s,3H), 6.80-7.20 (complex signal, 4H), 7.22 (m, 2H), 8.55 (d, J=8.0 Hz,2H).

EXAMPLE 1483-[N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amino]propan-1-ol

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 3-amino-1-propanol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 57%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.50-1.80 (complex signal,2H+NH+OH+H₂O), 2.91 (t, J=5.7 Hz, 2H), 3.31 (t, J=5.4 Hz, 2H), 3.77 (t,J=5.4 Hz, 2H), 4.54 (t, J=5.4 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.15 (m, 2H),7.29 (m, 2H), 7.82 (s, 1H), 8.31 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 149N-Ethyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 of section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and ethylamine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 58%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.09 (t, J=7.0 Hz, 3H), 1.71 (broad s,NH+H₂O), 2.70 (c, J=7.1 Hz, 2H), 3.29 (t, J=5.7 Hz, 2H), 4.56 (t, J=5.7Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz,2H), 7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.84 (s, 1H),8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1502-[N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amino]ethanol

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 2-aminoethanol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 54%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.70 (broad s, NH+OH+H₂O), 2.82 (t,J=5.3 Hz, 2H), 3.32 (t, J=5.6 Hz, 2H), 3.62 (t, J=5.3 Hz, 2H), 4.55 (t,J=5.6 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.83 (s,1H), 8.31 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 151N-[(2-Pyridyl)methyl]-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and (2-pyridyl)methylamine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 52%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.62 (broad s, NH+H₂O), 3.33 (t, J=5.7Hz, 2H), 3.92 (s, 2H), 4.58 (t, J=5.7 Hz, 2H), 6.83 (dd, J_(o)=1.8 Hz;J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 7.14(m, 4H), 7.29 (m, 2H), 7.60 (m, 1H), 7.86 (s, 1H), 8.31 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H), 8.51 (m, 1H).

EXAMPLE 152N-[(2-Thienyl)methyl]-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyland (2-thienyl)methylamine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 25%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.55 (broad s, NH+H₂O) 3.32 (t, J=5.6Hz, 2H), 4.00 (s, 2H), 4.54 (t, J=5.6 Hz, 2H), 6.83 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.91 (m, 1H), 7.00 (t, J=8.6Hz, 2H), 7.16 (m, 3H), 7.29 (m, 3H), 7.86 (s, 1H), 8.32 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1531-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidine-4-carboxamide

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and piperidine-4-carboxamide instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 75%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61-1.76 (complex signal, 5H), 1.84(m, 2H), 2.91 (m, 2H), 3.01 (t, J=6.3 Hz, 2H), 4.52 (t, J=6.3 Hz, 2H),5.27 (broad s, NH), 5.41 (broad s, NH), 6.83 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.02 (t, J=8.6 Hz, 2H), 7.14(m, 2H), 7.30 (m, 2H), 7.83 (s, 1H), 8.32 (dd, J_(o)=1.4 Hz, J_(m)=4.6Hz, 2H).

EXAMPLE 1544,6-Bis(4-fluorophenyl)-2-[2-(pyrrolidin-1-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and pyrrolidine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 75%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.77 (m, 4H), 2.55 (m, 4H), 3.17 (t,J=6.6 Hz, 2H), 4.58 (t, J=6.6 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 7.14 (m, 2H),7.29 (m, 2H), 7.84 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 155 (3R)-1-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]pyrrolidin-3-ol

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and (3R)-3-pyrrolidinol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 52%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.69 (broad s, 1H+OH+H₂O), 2.14 (m,1H), 2.40 (m, 1H), 2.58 (m, 1H), 2.69 (m, 1H), 2.94 (m, 1H), 3.20 (t,J=6.4 Hz, 2H), 4.32 (m, 1H), 4.57 (t, J=6.4 Hz, 2H), 6.83 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H),7.14 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

EXAMPLE 1562-[N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-N-methylamino]ethanol

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl,methanesulfonate and 2-(methylamino)ethanol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 71%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (broad s, OH+H₂O), 2.34 (s, 3H),2.60 (t, J=5.2 Hz, 2H), 3.14 (t, J=6.0 Hz, 2H), 3.53 (t, J=5.2 Hz, 2H),4.53 (t, J=6.0 Hz, 2H), 6.83 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H), 6.89(t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H),7.81 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1574,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-2-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 1,2,3,4-tetrahydroisoquinoline instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 57%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.78-2.85 (complex signal, 4H), 3.20(t, J=6.3 Hz, 2H), 3.72 (s, 2H), 4.63 (t, J=6.3 Hz, 2H), 6.81 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.86-7.17 (complex signal, 10H), 7.30(m, 2H), 7.86 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1584,6-Bis(4-fluorophenyl)-2-[2-(4-phenylpiperazin-1-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 1-phenylpiperazine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 71%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.69 (m, 4H), 3.10 (t, J=6.4 Hz, 2H),3.16 (m, 4H), 4.59 (t, J=6.4 Hz, 2H), 6.82 (dd, J_(o)=1.8 Hz, J_(m)=4.5Hz, 2H), 6.86-7.02 (complex signal, 9H), 7.14 (m, 2H), 7.29 (m, 2H),7.86 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1594,6-Bis(4-fluorophenyl)-2-[2-[4-(1-piperidyl)piperidin-1-yl]ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 4-piperidinopiperidine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 51%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.40-1.60 (complex signal, 8H), 1.78(m, 2H), 2.04-2.22 (complex signal, 3H), 2.48 (m, 4H), 2.96 (m, 4H),4.52 (t, J=6.4 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89(t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H),7.85 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1603-[N-[2-[4,6-Bis(4-Fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-N-methylamino]propiononitrile

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 3-(methylamino)propiononitrile instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 50%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.35 (complex signal, 5H), 2.71 (t,J=6.4 Hz, 4H), 3.13 (t, J=5.9 Hz, 2H), 4.50 (t, J=5.9 Hz, 2H), 6.83 (dd,J_(o)=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.17 (m, 2H), 7.31 (m, 2H), 7.87 (s, 1H), 8.32 (dd, J_(o)=1.5Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 161N-Methyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and methylamine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 51%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.61 (broad s, NH+H₂O), 3.25 (t, J=5.6Hz, 2H), 4.57 (t, J=5.6 Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz,2H), 6.90 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.29(m, 2H), 7.84 (s, 1H), 8.31 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1622-[2-[4-(tert-Butoxycarbonyl)piperazin-1-yl]ethyl]-4,6-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis(4-fluorophenyl)-5-(4-pyridil)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 1-(tert-butoxycarbonyl)piperazine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 63%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.45 (s, 9H), 2.46 (m, 4H), 3.05 (t,J=6.4 Hz, 2H), 3.40 (m, 4H), 4.54 (t, J=6.4 Hz, 2H), 6.82 (dd, J_(o)=1.6Hz, J_(m)=4.4 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H),7.15 (m, 2H), 7.30 (m, 2H), 7.86 (s, 1H), 8.33 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

EXAMPLE 1634,6-Bis(4-fluorophenyl)-2-[2-(piperazin-1-yl)ethyl]-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 36, but using2-[2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 162) instead of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine,the title compound was obtained (yield: 62%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.56 (broad s, NH+H₂O), 2.45 (m, 4H),2.85 (m, 4H), 3.00 (t, J=6.4 Hz, 2H), 4.55 (t, J=6.4 Hz, 2H), 6.82 (dd,J=1.6 Hz, J_(m)=4.4 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 7.03 (t, J=8.7 Hz,2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

EXAMPLE 1644,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-2-vinylpyrazolo[3,4-b]pyridine

A solution of2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (0.15 g, 0.3 mmol, obtained in example 116 section a)and KOH (0.02 g, 0.3 mmol) in toluene (4 mL) was heated to 100° C.reflux overnight. Water and EtOAc were added and the phases wereseparated. The aqueous phase was saturated with NaCl (solid) andextracted with EtOAc. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 110 mg of the title compound (yield: 90%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 5.27 (dd, J_(gem)=1.8 Hz, J_(vec)=8.7Hz, 1H), 6.22 (dd, J_(gem)=1.4 Hz, J_(vec)=15.4 Hz, 1H), 6.83 (dd,J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.91 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.15 (m, 2H), 7.17-7.34 (complex signal, 3H), 7.90 (s, 1H),8.33 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 1652-[N-[2-[4,6-Bis-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-N-(2-hydroxyethyl)amino]ethanol

Following a similar procedure to that described in example 111, butusing2-[4,6-bis-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and 2-(2-hydroxyethylamino)ethanol instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 51%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.50 (broad s, 20H+H₂O), 2.73 (t, J=5.0Hz, 4H), 3.21 (t, J=5.6 Hz, 2H), 3.52 (t, J=5.0 Hz, 4H), 4.54 (t, J=5.4Hz, 2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.89 (t, J=8.7 Hz,2H), 6.99 (t, J=8.7 Hz, 2H), 7.13 (M, 2H), 7.29 (m, 2H), 7.89 (s, 1H),8.32 (dd, J_(o)=1.8 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 166N-Cyclopropyl-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]amine

Following a similar procedure to that described in example 111, butusing2-[4,6-bis-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in example 116 section a) instead of3-[4,6-bis-(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propylmethanesulfonate and cyclopropylamine instead ofN-(tert-butoxycarbonyl)-N-(4-piperidyl)amine, the desired compound wasobtained (yield: 47%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 0.30 (m, 2H), 0.45 (m, 2H), 1.60 (broads, NH+H₂O), 2.20 (m, 1H), 3.36 (t, J=5.7 Hz, 2H), 4.55 (t, J=5.7 Hz,2H), 6.82 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 6.90 (t, J=8.7 Hz, 2H),7.00 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.82 (s, 1H), 8.32(dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLE 167N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]acetamide

Following a similar procedure to that described in reference example 1section a, but using acetyl chloride instead of 4-fluorobenzoyl chlorideand2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 90) instead of N,O-dimethylhydroxylamine, thedesired compound was obtained (yield: 48%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.98 (s, 3H), 3.95 (m, 2H), 4.58 (t,J=5.4 Hz, 2H), 6.47 (m, NH), 6.83 (d, J=9.0 Hz, 2H), 6.91 (t, J=8.7 Hz,2H), 7.01 (t, J=8.6 Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.82 (s, 1H),8.33 (d, J=9.0 Hz, 2H).

EXAMPLE 168N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-N-isopropylurea

To a solution of2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.06 g, 0.15 mmol, obtained in example 90) in DMF (1 mL),isopropylisocyanate (0.02 g, 0.18 mmol) was added under argonatmosphere. This was stirred at room temperature for 2 days. The solventwas concentrated again and diethyl ether was added to the residueobtained. The solvent was concentrated, to afford 38 mg of titlecompound in solid form (yield: 50%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.05 (d, J=6.3 Hz, 6H), 3.84 (m, 3H),4.22 (m, NH), 4.58 (t, J=5.4 Hz, 2H), 5.30 (m, NH), 6.82 (dd, J_(o)=1.4Hz, J_(m)=4.6 Hz, 2H), 6.91 (t, J=8.7 Hz, 2H), 7.00 (t, J=8.6 Hz, 2H),7.13 (m, 2H), 7.28 (m, 2H), 7.84 (s, 1H), 8.32 (dd, J_(o)=1.5 Hz,J_(m)=4.5 Hz, 2H).

EXAMPLE 169N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]methanesulfonamide

To a solution of2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(0.06 g, 0.15 mmol, obtained in example 90) and DMAP (0.001 g, 0.0058mmol) in pyridine (0.6 mL), methanesulfonyl chloride (0.017 mL, 0.22mmol) was added under argon atmosphere and cooled with an ice bath(0.017 mL, 0.22 mmol). This was stirred overnight at room temperature.The solvent was concentrated. The residue was dissolved in CHCl₃ andsaturated NaHCO₃ was added. The phases were separated. The organic phasewas dried over Na₂SO₄ and concentrated. The crude product obtained waspurified by chromatography on silica gel using EtOAc as solvent, and 70mg of the title compound was obtained (yield: 95%).

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.99 (s, 3H), 3.86 (m, 2H), 4.64 (t,J=5.3 Hz, 2H), 5.33 (m, NH), 6.83 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H),6.91 (t, J=8.7 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 7.14 (m, 2H), 7.29 (m,2H), 7.88 (s, 1H), 8.33 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

EXAMPLEs 170-178

Following a similar procedure to that described in example 72, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS t_(R) m/z Example Compound name Starting compounds Method (min)[M + H]⁺ 170 6-(4-Fluorophenyl)-4-(4- Reference example 1,3- 1 3.34374.1 piperidyl)-5-(4-pyridyl)-1H- amino-2H-pyrazole andpyrazolo[3,4-b]pyridine 1-(tert-butoxycarbonyl)- piperidine-4-carbaldehyde 171 6-(4-Fluorophenyl)-4-(2- Reference example 1,3- 1 5.72357.1 furyl)-5-(4-pyridyl)-1H- amino-2H-pyrazole andpyrazolo[3,4-b]pyridine furan-2-carbaldehyde 1726-(4-Fluorophenyl)-4-(1H- Reference example 1,3- 1 3.25 357.1imidazol-4-yl)-5-(4-pyridyl)- amino-2H-pyrazole and1H-pyrazolo[3,4-b]pyridine 2H-pyrazole-3- carbaldehyde 1734-(5-Bromothien-2-yl)-6-(4- Reference example 1,3- 1 7.46 450.9fluorophenyl)-5-(4-pyridyl)- amino-2H-pyrazole and 452.91H-pyrazolo[3,4-b]pyridine 5-bromothiophene-2- carbaldehyde 1744,6-Bis(4-fluorophenyl)-5- Reference example 19, 1 9.11 432.2(2-methylsulfanylpyrimidin- 3-amino-2H-pyrazole and4-yl)-1H-pyrazolo[3,4- 4-fluorobenzaldehyde b]pyridine 1755-(2-Chloropyridin-4-yl)- Reference example 23, 1 8.99 419.04,6-bis(4-fluorophenyl)-1H- 3-amino-2H-pyrazole and 421.0pyrazolo[3,4-b]pyridine 4-fluorobenzaldehyde 1766-(4-Fluorophenyl)-4-(2- Reference example 1,3- 1 6.52 395.0phenylethyl)-5-(4-pyridyl)- amino-2H-pyrazole and1H-pyrazolo[3,4-b]pyridine 3-phenylpropionaldehyde 1774-(6-Chloropyridin-3-yl)-6- Reference example 1,6- 1 5.50 402.0(4-fluorophenyl)-5-(4- chloropyridine-3- 404.0 pyridyl)-1H-pyrazolo[3,4-carbaldehyde and amino- b]pyridine 2H-pyrazole 1784-(3,4-Dichlorophenyl)-1- Reference example 1, 1 10.56 462.9ethyl-6-(4-fluorophenyl)-5- 3,4-dichlorobenzaldehyde 464.9(4-pyridyl)pyrazolo[3,4- and 3-amino-2- b]pyridine ethylpyrazole

EXAMPLE 1796-(4-Fluorophenyl)-4-(1-methylpiperidin-4-yl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine

To a suspension of6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.24 g, 0.6 mmol, obtained in example 170) in formic acid (0.64 mL),35-40% aqueous formaldehyde (0.96 mL) was added. It was heated to 70-80°C. for 24 h. It was allowed to cool and 1 N NaOH was added. It wasextracted with CHCl₃ and the combined organic phases were dried overNa₂SO₄ and concentrated to dryness. The crude product obtained waspurified by chromatography on silica gel using CHCl₃-MeOH—NH₃ mixturesof increasing polarity as eluent, to afford 47 mg of the desiredcompound (yield: 19%).

LC-MS (method 1): t_(R)=3.28 min; m/z=388.1 [M+H]⁺.

EXAMPLE 1803-Amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in reference example 15section c, but using2-chloro-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyridine-3-carbonitrile(obtained in reference example 22) instead of3-(1-benzylpiperidin-4-yl)-3-oxopropiononitrile, the title compound wasobtained,

LC-MS (method 1): t_(R)=6.70 min; m/z=353.0 [M+H]⁺.

EXAMPLE 1816-(4-Fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine

To a solution of3-amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridine(10.00 g, 28.4 mmol, obtained in example 180) in AcOH (52 mL), water (22mL) and HCl conc. (5.7 mL), cooled to 0° C., a solution of NaNO₂ (2.30g, 33.4 mmol) in water (7.5 mL) was added dropwise. It was stirred for30 min at 0° C., and H₃PO₂ (50% aqueous solution, 56.8 mL) was addedslowly. It was stirred at 0° C. for 6 h. It was allowed to cool to roomtemperature, basified at 0° C. by slow addition of 6 N NaOH hasta pH=8and was extracted with EtOAc. The combined organic phases were driedover Na₂SO₄ and concentrated to dryness. The crude product obtained waspurified by chromatography on silica gel using hexane-EtOAc mixtures ofincreasing polarity as eluent, to afford 4.00 g of the title compound(yield: 42%)

LC-MS (method 1): t_(R)=7.80 min; m/z=338.0 [M+H]⁺.

EXAMPLEs 182-193

Following a similar procedure to that described in examples 6 and 7, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS t_(R) m/z Example Compound name Starting compounds Method (min)[M + H]⁺ 182 4,6-Diphenyl-5-(4-pyridyl)-2-[2- Example 2 and 2-(2- 1 6.70477.1 (tetrahydropyran-2-yloxy)ethyl]- bromoethoxy)tetra-pyrazolo[3,4-b]pyridine hydropyran 183 6-(4-Fluorophenyl)-4-(2-furyl)-2-Example 171 and 1 5.32 371.1 methyl-5-(4-pyridyl)pyrazolo[3,4-iodomethane b]pyridine 184 6-(4-Fluorophenyl)-2-methyl-4-(1- Example 172and 1 3.66 385.2 methyl-1H-imidazol-4-yl)-5-(4- iodomethane (2pyridyl)pyrazolo[3,4-b]pyridine equivalents) 1856-(4-Fluorophenyl)-5-(2- Example 181 and 2- 1 8.79 466.1methylsulfanylpyrimidin-4-yl)-2- (2-bromoethoxy)- [2-(tetrahydropyran-2-tetrahydropyran yloxy)ethyl]-pyrazolo[3,4- b]pyridine 1866-(4-Fluorophenyl)-5-(2- Example 181 and 2- 1 9.11 480.2methylsulfanylpyrimidin-4-yl)-2- (3-bromopropoxy)-[3-(tetrahydropyran-2- tetrahydropyran yloxy)propyl]-pyrazolo[3,4-b]pyridine 187 4,6-Bis(4-fluorophenyl)-5-(2- Example 174 and 2- 1 10.26574.2 methylsulfanylpyrimidin-4-yl)-2- (3-bromopropoxy)-[3-(tetrahydropyran-2- tetrahydropyran yloxy)propyl]-pyrazolo[3,4-b]pyridine 188 4-(5-Bromothien-2-yl)-6-(4-fluoro- Example 173 and 1 6.94464.9 phenyl)-2-methyl-5-(4-pyridyl)- iodomethane 466.91H-pyrazolo[3,4-b]pyridine 189 6-(4-Fluorophenyl)-2-methyl-5-(2- Example181 and 1 7.29 352.0 methylsulfanylpyrimidin-4- iodomethaneyl)pyrazolo[3,4-b]pyridine 190 5-(2-Chloropyridin-4-yl)-4,6-bis(4-Example 175 and 1 8.55 433.0 fluorophenyl)-2-methylpyrazolo- iodomethane435.0 [3,4-b]pyridine 191 6-(4-Fluorophenyl)-4-(2-phenyl- Example 176and 2- 1 7.74 537.0 ethyl)-5-(4-pyridyl)-2-[3- (3-bromopropoxy)-(tetrahydropyran-2-yloxy)propyl]- tetrahydropyranpyrazolo[3,4-b]pyridine 192 4-(6-Chloropyridin-3-yl)-6-(4- Example 177and 2- 1 9.05 544.2 fluorophenyl)-5-(4-pyridyl)-2-[3- (3-bromopropoxy)-546.2 (tetrahydropyran-2-yloxy)propyl]- tetrahydropyranpyrazolo[3,4-b]pyridine 193 4-(6-Chloropyridin-3-yl)-6-(4- Example 177and 1 5.34 416.1 fluorophenyl)-2-methyl-5-(4- iodomethane 418.1pyridyl)pyrazolo[3,4-b]pyridine

EXAMPLE 1945-(2-Methylsulfanylpyrimidin-4-yl)-2-[3-(tetrahydropyran-2-yloxy)propyl]-6-(3-trifluoromethylphenyl)pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butstarting from5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(obtained in example 126) and 2-(3-bromopropoxy)tetrahydropyran, thetitle compound was obtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 1.50-1.90 (m, 4H), 2.40 (complexsignal, 5H), 3.37-3.50 (m, 4H), 3.85 (m, 2H), 4.53 (m, 1H), 4.65 (m,2H), 6.68 (d, J=5.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.6 Hz,1H), 7.61 (d, J=7.5 Hz, 1H), 7.93 (s, 1H), 8.13 (s, 1H), 8.32 (d, J=5.1Hz, 1H), 8.49 (s, 1H).

EXAMPLE 1956-(4-Fluorophenyl)-2-methyl-5-(4-pyridyl)-4-[5-(3-pyridyl)thien-2-yl]pyrazolo[3,4-b]pyridine

A suspension of4-(5-bromothien-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.10 g, 0.2 mmol, obtained in example 188), 3-pyridylboronic acid (0.04g, 0.3 mmol), K₂CO₃ (0.06 g, 0.4 mmol), Pd(PPh₃)₄ (0.017 g, 0.01 mmol),1,2-dimethoxyethane (1.31 mL) and water (0.04 mL) was heated at 80° C.under argon atmosphere overnight. It was allowed to cool and dilutedwith CHCl₃ and water. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures of increasingpolarity as eluent, to afford 35 mg of the desired compound (yield:50%).

LC-MS (method 1): t_(R)=5.42 min; m/z=464.0 [M+H]⁺.

EXAMPLEs 196-202

Following a similar procedure to that described in example 91 but usingthe adequate starting compounds in each case, the compounds in thefollowing table were obtained:

LC-MS Starting t_(R) m/z Example Compound name compound Method (min)[M + H]⁺ 196 2-[4,6-Diphenyl-5-(4-pyridyl)pyrazolo- Example 182 1 4.67393.0 [3,4-b]pyridin-2-yl]ethanol 1973-[5-(2-Methylsulfanylpyrimidin-4-yl)-6- Example 194 1 7.67 446.0(3-trifluoromethylphenyl)pyrazolo-[3,4- b]pyridin-2-yl]propan-1-ol 1982-[6-(4-Fluorophenyl)-5-(2-methyl- Example 185 1 6.58 382.0sulfanylpyrimidin-4-yl)pyrazolo[3,4- b]pyridin-2-yl]ethanol 1993-[6-(4-Fluorophenyl)-5-(2-methyl- Example 186 1 6.79 396.1sulfanylpyrimidin-4-yl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol 2003-[4,6-Bis(4-fluorophenyl)-5-(2-methyl- Example 187 1 8.10 490.2sulfanylpyrimidin-4-yl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol 2013-[6-(4-Fluorophenyl)-4-(2- Example 191 1 5.80 453.2phenylethyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol 2023-[4-(6-Chloropyridin-3-yl)-6-(4- Example 192 1 5.88 460.2fluorophenyl)-5-(4-pyridyl)pyrazolo- 462.2[3,4-b]pyridin-2-yl]propan-1-ol

EXAMPLEs 203-207

Following a similar procedure to that described in example 56 but usingthe adequate starting compounds in each case, the compounds in thefollowing table were obtained:

LC-MS Starting t_(R) m/z Example Compound name compound Method (min)[M + H]⁺ 203 6-(4-Fluorophenyl)-2-methyl-5-(2- Example 189 1 5.76 384.0methylsulfonylpyrimidin-4- yl)pyrazolo[3,4-b]pyridine 2043-[5-(2-Methylsulfonylpyrimidin-4-yl)-6- Example 197 1 6.39 478.0(3-trifluoromethylphenyl)pyrazolo-[3,4- b]pyridin-2-yl]propan-1-ol 2052-[6-(4-Fluorophenyl)-5-(2-methyl- Example 198 1 5.28 414.0sulfonylpyrimidin-4-yl)pyrazolo[3,4- b]pyridin-2-yl]ethanol 2063-[6-(4-Fluorophenyl)-5-(2-methyl- Example 199 1 5.46 428.0sulfonylpyrimidin-4-yl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol 2073-[4,6-Bis(4-fluorophenyl)-5-(2-methyl- Example 200 1 6.76 522.2sulfonylpyrimidin-4-yl)pyrazolo[3,4- b]pyridin-2-yl]propan-1-ol

EXAMPLE 208N-Cyclopropylmethyl-[4-[6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2-yl]amine

A solution of5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(90 mg, 0.2 mmol, obtained in example 127) and (cyclopropylmethyl)amine(75 mg, 1.0 mmol) in THF (2 mL) was heated in a closed vessel at 60° C.overnight. It was allowed to cool and concentrated. The crude productobtained was purified by chromatography on silica gel using hexane-EtOAcmixtures of increasing polarity as eluent, to afford 57 mg of thedesired compound (yield: 67%).

LC-MS (method 1): t_(R)=8.12 min; m/z=411.0 [M+H]⁺.

Following a similar procedure to that described in example 208 but usingthe adequate starting compounds in each case, the compounds in thefollowing table were obtained:

LC-MS Starting m/z Example Compound name compound Method t_(R) (min)[M + H]⁺ 209 (1S)-3-[5-[2-(1-Phenylethylamino)- Example 204 1 9.11 519.1pyrimidin-4-yl]-6-(3-trifluoromethyl- and (1S)-1-phenyl)pyrazolo[3,4-b]pyridin-2- phenylethyl- yl]propan-1-ol amine 210N-Cyclopropylmethyl-[4-[6-(4- Example 203 1 6.43 375.1fluorophenyl)-2-methylpyrazolo[3,4- andb]pyridin-5-yl]pyrimidin-2-yl]amine (cyclopropyl- methyl)amine 2112-[5-[2-[(Cyclopropylmethyl)- Example 205 1 5.85 405.1amino]pyrimidin-4-yl]-6-(4-fluoro- and phenyl)pyrazolo[3,4-b]pyridin-2-(cyclopropyl- yl]ethanol methyl)amine 212 3-[5-[2-[(Cyclopropylmethyl)-Example 206 1 6.06 419.1 amino]pyrimidin-4-yl]-6-(4-fluoro- andphenyl)pyrazolo[3,4-b]pyridin-2- (cyclopropyl- yl]propan-1-olmethyl)amine 213 3-[5-[2-[(Cyclopropylmethyl)amino]- Example 207 1 7.63513.3 pyrimidin-4-yl]-4,6-bis(4-fluoro- andphenyl)pyrazolo[3,4-b]pyridin-2- (cyclopropyl- yl]propan-1-olmethyl)amine

EXAMPLE 2144-[4-[4,6-Bis(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridin-5-yl]pyridin-2-ylamino]benzenesulfonamide

A mixture of5-(2-chloropyridin-4-yl)-4,6-bis(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine(100 mg, 0.23 mmol, obtained in example 190) and4-aminobenzenesulfonamide (46 mg, 0.27 mmol) was heated at 190° C.overnight. It was allowed to cool and the crude product obtained waspurified by chromatography on silica gel using EtOAc as eluent, toafford 23 mg of the desired compound (yield: 17%).

LC-MS (method 1): t_(R)=6.91 min; m/z=569.0 [M+H]⁺.

EXAMPLEs 215-230

Following a similar procedure to that described in example 72 but usingthe adequate starting compounds in each case, the compounds in thefollowing tables were obtained:

LC-MS t_(R) m/z Example Compound name Starting compounds Method (min)[M + H]⁺ 215 4,6-Bis(4-fluorophenyl)-5- Reference example 1, 5- 1 5.02401.1 (4-pyridyl)pyrazolo-[3,4- amino-1H-pirazol-3-ol and b]pyridin-3-ol4-fluorobenzaldehyde 216 6-(4-Fluoropheny)-4- Reference example 1, 3- 13.23 357.1 (3H-imidazol-4-yl)-5-(4- amino-2H-pyrazole and 3H-pyridyl)-1H-pyrazolo[3,4- imidazol-4-carbaldehyde b]pyridine 2176-(4-Fluorophenyl)-4- Reference example 1, 3- 1 4.24 357.1(1H-pyrazol-3-yl)-5-(4- amino-2H-pyrazole and 2H-pyridyl)-1H-pyrazolo[3,4- pyrazole-3-carbaldehyde b]pyridine 2183-[6-(4-Fluorophenyl)-5- Reference example 1, 3- 1 4.99 383.1(4-pyridyl)-1H-pyrazolo- amino-2H-pyrazole and 3-[3,4-b]pyridin-4-yl]phenol Hydroxybenzaldehyde 219 4-Cyclopropyl-6-(4-Reference example 1, 3- 1 4.99 331.1 fluorophenyl)-5-(4-amino-2H-pyrazole and pyridyl)-1H-pyrazolo[3,4- cyclopropanecarbaldehydeb]pyridine 220 6-(4-Fluorophenyl)-4-(5- Reference example 1, 3- 1 8.45445 methylfuran-2-yl)-5-(4- amino-2H-pyrazole and 5-pyridyl)-1H-pyrazolo[3,4- methylfuran-2-carbaldehyde b]pyridine 2214-(5-Bromofuran-2-yl)-6- Reference example 1, 3- 1 7.02 435.0(4-fluorophenyl)-5-(4- amino-2H-pyrazole and 5- 437.0pyridyl)-1H-pyrazolo[3,4- methylfuran-2-carbaldehyde b]pyridine 2224-(4-Benzyloxyphenyl)-6- Reference example 30, 3- 1 9.05 474.1(4-fluorophenyl)-2- amino-2H-pyrazole and 4- methyl-5-pyrimidin-4-yl-benzyloxybenzaldehyde 1H-pyrazolo[3,4- b]pyridine 2234-(4-Benzyloxyphenyl)-6- Reference example 19, 3- 1 10.52 520.1(4-fluorophenyl)-5-(2- amino-2H-pyrazale and 4- methylsulfanylpyrimidin-benzyloxybenzaldehyde 4-yl)-1H-pyrazolo[3,4- b]pyridine 2246-(4-Fluorophenyl)-4- Reference example 1, 3- 1 5.42 333.0propyl-5-(4-pyridyl)-1H- amino-2H-pyrazole and pyrazolo[3,4-b]pyridinebutyraldehyde 225 4-(3-Benzyloxyphenyl)-6- Reference example 1, 3- 18.00 473.2 (4-fluorophenyl)-5-(4- amino-2H-pyrazole and 3-pyridyl)-1H-pyrazolo[3,4- benzyloxybenzaldehyde b]pyridine 2265-(2-Chloropyridin-4-yl)- Reference example 23, 3- 1 7.73 325.26-(4-fluorophenyl)-1H- amino-2H-pyrazole and 327.2pyrazolo[3,4-b]pyridine paraformaldehyde 227 4-[6-(4-Fluorophenyl)-5-Reference example 1, 3- 1 4.23 363.2 (4-pyridyl)-1H- amino-2H-pyrazoleand 5- pyrazolo[3,4-b]pyridin-4- hydroxypentanal yl]butan-1-ol 2284-Benzyl-6-(4- Reference example 1, 3- 1 6.37 381.2 fluorophenyl)-5-(4-amino-2H-pyrazole and pyridyl)-1H-pyrazolo[3,4- phenylacetaldehydeb]pyridine Starting Example Compound name compounds ¹H NMR (300 MHz,CDCl₃) δ (TMS) 229 4-(4-Benzyloxyphenyl)- Reference example 5.06 (s,2H), 6.85 (dd, J_(o) = 1.5 Hz, 6-(4-fluorophenyl)-2- 1, 3-amino-2H-J_(m) = 4.5 Hz, 2H), 6.91 (m, 4H), methyl-5-(4-pyridyl)-1H- pyrazole and4- 6.95 (m, 2H), 7.23-7.40 (m, 7H), pyrazolo[3,4-b]pyridine benzyloxy-8.01 (s, 1H), 8.35 (dd, J_(o) = 1.5 Hz, benzaldehyde J_(m) = 4.5 Hz,2H), 10.62 (broad s, 1H, NH). 230 4,6-Bis(4-fluorophenyl)- Referenceexample 6.92-7.08 (complex signal, 5H), 5-pyrimidin-4-yl-1H- 30,3-amino-2H- 7.23 (m, 2H), 7.32 (m, 2H), pyrazolo[3,4-b]pyridine pyrazoleand 4- 7.99 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), fluorobenzaldehyde 9.03(s, 1H), 11.40 (broad s, 1H, NH).

EXAMPLE 231[(2S)-2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]pyrrolidine-2-carboxamidea)[(2S)-2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-1-(benzyloxycarbonyl)pyrrolidine-2-carboxamide

Following a similar procedure to that described in example 48, butstarting from2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 90) and(2S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid, the desiredcompound was obtained.

LC-MS (method 1): t_(R)=7.13 min; m/z=659.3 [M+H]⁺.

b) Title Compound

Following a similar procedure to that described in example 269, butstarting from[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-1-(benzyloxycarbonyl)pyrrolidine-2-carboxamide(obtained in section a), the title compound was obtained.

LC-MS (method 1): t_(R)=4.35 min; m/z=525.2 [M+H]⁺.

EXAMPLE 2322-[2-(4,6-Diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl)ethylamino]ethanola) 2-[4,6-Diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate

Following a similar procedure to that described in example 12 section b,but starting from2-[4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethanol(obtained in example 196), the desired compound was obtained.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 2.94 (s, 3H), 4.76 (m, 2H), 4.85 (m,2H), 6.88 (d, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H), 7.15-7.90 (complexsignal, 10H), 8.27 (s, 1H), 8.28 (dd, J_(o)=1.5 Hz, J_(m)=4.5 Hz, 2H).

b) Title Compound

Following a similar procedure to that described in example 111, butstarting from2-[4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethylmethanesulfonate (obtained in section a) and 2-amino-1-ethanol, thedesired compound was obtained.

LC-MS (method 1): t_(R)=3.89 min; m/z=436.1 [M+H]⁺.

EXAMPLE 2336-(4-Fluorophenyl)-2-methyl-4-(3-pyridyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine

To a solution of4-(6-chloropyridin-3-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(74 mg, 0.2 mmol, obtained in example 193) in AcOH (1 mL), Zn (72 mg,1.1 mmol) was added under argon atmosphere and the mixture was heated toreflux overnight. It was allowed to cool and concentrated. The residuewas treated with saturated NaHCO₃ and it was extracted with CHCl₃. Theorganic phase was dried over Na₂SO₄ and concentrated to dryness. Thecrude product obtained was purified by chromatography on silica gelusing hexane-EtOAc-MeOH mixtures of increasing polarity, to afford 2.4mg of the title compound (yield: 4%)

LC-MS (method 1): t_(R)=4.02 min; m/z=382.2 [M+H]⁺.

EXAMPLEs 234-235

Following a similar procedure to that described in reference example 15section c, but starting from the appropriate compounds in each case, thecompounds in the following table were obtained:

LC-MS m/z Example Compound name Starting compounds Method t_(R) (min)[M + H]⁺ 234 6-(4-Fluorophenyl)-3-methyl- Reference example 1 8.57 352.05-(2-methylsulfanylpyrimidin- 29 and hydrazine 4-yl)-1H-pyrazolo[3,4-monohydrate b]pyridine 235 3-Amino-5-(2-methylsulfanyl- Referenceexample 1 6.55 335.0 pyrimidin-4-yl)-6-phenyl-1H- 28 and hydrazinepyrazolo[3,4-b]pyridine monohydrate

EXAMPLEs 236-237

Following a similar procedure to that described in example 77, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS Starting m/z Example Compound name compound Method t_(R) (min)[M + H]⁺ 236 5-(2-Methylsulfanylpyrimidin-4-yl)-6- Example 235 1 7.54320.0 phenyl-1H-pyrazolo[3,4-b]pyridine 2376-(4-Fluorophenyl)-4-methyl-5-(2- Example 147 1 4.42 305.0methylsulfanylpyrimidin-4-yl)-1H- pyrazolo[3,4-b]pyridine

EXAMPLE 2385-(2-Methoxypyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridine

To a solution of5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(90 mg, 0.2 mmol, obtained in example 127) in MeOH (5 mL) in a closedvessel, sodium methoxide (11 mg, 0.2 mmol) was added and heated to 60°C. for 24 h. Then, sodium methoxide (11 mg, 0.2 mmol) was added and itwas stirred at 60° C. for 2 h more. It was allowed to cool and wasconcentrated. EtOAc and buffer (pH=5.3) were added. The phases wereseparated and the organic phase was washed with water, dried over Na₂SO₄and concentrated to dryness. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc mixtures at 50%, toafford 38 mg of the title compound (yield: 47%)

LC-MS (method 1): t_(R)=7.71 min; m/z=372.0 [M+H]⁺.

EXAMPLEs 239-242

Following a similar procedure to that described in reference example 1section a, but starting from the appropriate compounds in each case, thecompounds in the following table were obtained:

LC-MS Starting m/z Example Compound name compound Method t_(R) (min)[M + H]⁺ 239 N-[2-[4,6-(Diphenyl)-5-(4- Example 142 and 1 5.34 434.1pyridyl)pyrazolo[3,4-b]pyridin-2- acetyl chloride yl]ethyl]acetamide 240N-[3-[4,6-Bis(4-fluorophenyl)-5- Example 95 and 1 5.31 484.1(4-pyridyl)pyrazolo[3,4-b]pyridin- acetyl chloride 2-yl]propyl]acetamide241 N-[2-(4,6-Diphenyl-5-(4- Example 232 and 1 5.27 478.1pyridyl)pyrazolo[3,4-b]pyridin-2- acetyl chlorideyl)ethyl]-N-(2-hydroxyethyl)- acetamide 242N-[2-[4,6-Bis(4-fluorophenyl)-5- Example 90 and 1 5.39 484.1(4-pyridyl)pyrazolo[3,4-b]pyridin- propionyl chloride2-yl]ethyl]propionamide

EXAMPLE 243N-[3-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propyl]methanesulfonamide

Following a similar procedure to that described in example 169, butstarting from2-(3-aminopropyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 95), the desired compound was obtained.

LC-MS (method 1): t_(R)=5.79 min; m/z=520.1 [M+H]⁺.

EXAMPLE 2445-(2-Aminopyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridine

A solution of THF (20 mL) saturated with NH₃ (g) at −20° C. was addedover5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(90 mg, 0.2 mmol, obtained in example 127) in a closed vessel. It wasstirred at room temperature for 2 days and concentrated. The crudeproduct obtained was purified by chromatography on silica gel usinghexane-EtOAc mixtures of increasing polarity as eluent, to afford 7 mgof the title compound (yield: 9%)

LC-MS (method 1): t_(R)=6.01 min; m/z=357.0 [M+H]⁺.

EXAMPLE 245N-[5-(2-Methylsulfanylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide

A solution of3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(200 mg, 0.5 mmol, obtained in example 123) and acetyl chloride (39 mg,0.5 mmol) in pyridine (10 mL) was stirred at room temperature for 3 h.It was concentrated and the residue was taken up in a mixture of EtOAcand 1 N NaOH. The organic phase was dried over Na₂SO₄ and concentratedto dryness. The crude product obtained was purified by chromatography onsilica gel using hexane-EtOAc mixtures of increasing polarity as eluent,to afford 78 mg of the title compound (yield: 37%)

LC-MS (method 1): t_(R)=8.55 min; m/z=445.0 [M+H]⁺.

EXAMPLE 246N-Cyclopropylmethyl-[4-[3-benzyloxycarbonylamino-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2-yl]aminea)N-Benzyloxycarbonyl-[5-(2-methylsulfanylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amine

Following a similar procedure to that described in example 245, butstarting from3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine(obtained in example 123) and benzyl chloroformate, the desired compoundwas obtained.

LC-MS (method 1): t_(R)=10.00 min; m/z=537.1 [M+H]⁺.

b)N-Benzyloxycarbonyl-[5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amine

Following a similar procedure to that described in example 56, butstarting fromN-benzyloxycarbonyl-[5-(2-methylsulfanylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amine(obtained in section a), the desired compound was obtained.

LC-MS (method 1): t_(R)=8.47 min; m/z=567.1 [M+H]⁺.

c) Title Compound

Following a similar procedure to that described in example 208, butstarting fromN-benzyloxycarbonyl-[5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amine(obtained in section b) and (cyclopropylmethyl)amine, the desiredcompound was obtained.

LC-MS (method 1): t_(R)=9.44 min; m/z 560.3 [M+H]⁺.

EXAMPLE 247N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-2-hydroxyacetamide

Following a similar procedure to that described in example 48, butstarting from2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 90) and hydroxyacetic acid, the title compound wasobtained.

LC-MS (method 1): t_(R)=4.84 min; m/z=486.1 [M+H]⁺.

EXAMPLE 248N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidine-4-carboxamidea)N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxamide

Following a similar procedure to that described in example 48, butstarting from2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 90) and1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, the desiredcompound was obtained.

b) Title Compound

Following a similar procedure to that described in example 36, butstarting fromN-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxamide(obtained in section a), the title compound was obtained.

LC-MS (method 1): t_(R)=4.29 min; m/z=539.2 [M+H]⁺.

EXAMPLE 249N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-2-(methylamino)acetamidea)N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-2-chloroacetamide

Following a similar procedure to that described in reference example 1section a, but starting from2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 90) and chloroacetyl chloride, the title compoundwas obtained.

LC-MS (method 1): t_(R)=5.72 min; m/z 504.1, 506.1 [M+H]⁺.

b) Title Compound

Following a similar procedure to that described in example 78, butstarting fromN-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-2-chloroacetamide(obtained in section a) and methylamine, the title compound wasobtained.

LC-MS (method 1): t_(R)=4.28 min; m/z=499.2 [M+H]⁺.

EXAMPLE 250N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-2-(2-hydroxyethylamino)acetamide

Following a similar procedure to that described in example 78, butstarting fromN-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]-2-chloroacetamide(obtained in example 249 section a) and 2-aminoethanol, the titlecompound was obtained.

LC-MS (method 1): t_(R)=4.29 min; m/z=529.2 [M+H]⁺.

EXAMPLE 251N-[2-[4,6-Bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]nicotinamidea) Nicotinoyl chloride hydrochloride

A solution of nicotinic acid (0.50 g, 4.0 mmol) and POCl₃ (5 mL) washeated at reflux for 1.5 h and concentrated. The product obtained wasdirectly used in the next reaction.

b) Title Compound

Following a similar procedure to that described in example 245, butstarting from2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(obtained in example 90) and nicotinoyl chloride hydrichloride (obtainedin section a), the title compound was obtained.

LC-MS (method 1): t_(R)=5.25 min; m/z=533.1 [M+H]⁺.

EXAMPLEs 252-265

Following a similar procedure to that described in examples 6 and 7, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS Starting m/z Example Compound name compound Method t_(R) (min)[M + H]⁺ 252 4-(4-Benzyloxyphenyl)-6-(4-fluoro- Example 229 1 7.53 487.1phenyl)-2-methyl-5-(4-pyridyl)- and pyrazolo[3,4-b]pyridine iodomethane253 6-(4-Fluorophenyl)-5-(2-methyl- Example 181 1 7.13 352.1sulfanylpyrimidin-4-yl)-2-methyl- and pyrazolo[3,4-b]pyridineiodomethane 254 6-(4-Fluorophenyl)-2,4-dimethyl-5-(4- Example 237 1 4.11319.00 pyridyl)pyrazolo[3,4-b]pyridine and iodomethane 2554-(4-Benzyloxyphenyl)-6-(4-fluoro- Example 223 1 10.16 534.2phenyl)-2-methyl-5-(2-methylsulfanyl- andpyrimidin-4-yl)pyrazolo[3,4-b]pyridine iodomethane 2562-(1-Benzylpyrrolidin-2-ylmethyl)-4,6- Example 1 1 6.10 558.2bis(4-fluorophenyl)-5-(4-pyridyl)- and 1-benzyl- pyrazolo[3,4-b]pyridine2-chloro- methyl- pyrrolidine 257 4-(4-Benzyloxyphenyl)-6-(4-fluoro-Example 222 1 8.72 488.2 phenyl)-2-methyl-5-pyrimidin-4- andylpyrazolo[3,4-b]pyridine iodomethane 2586-(4-Fluorophenyl)-2-methyl-4-(5- Example 220 1 5.85 385.0methylfuran-2-yl)-5-(4-pyridyl)- and pyrazolo[3,4-b]pyridine iodomethane259 4-(5-Bromofuran-2-yl)-6-(4-fluoro- Example 221 1 6.48 449.1phenyl)-2-methyl-5-(4-pyridyl)- and 451.1 pyrazolo[3,4-b]pyridineiodomethane 260 6-(4-Fluorophenyl)-2-methyl-4-propyl- Example 224 1 4.88347.0 5-(4-pyridyl)pyrazolo[3,4-b]pyridine and iodomethane 2614-(3-Benzyloxyphenyl)-6-(4-fluoro- Example 225 1 7.79 487.0phenyl)-2-methyl-5-(4-pyridyl)- and pyrazolo[3,4-b]pyridine iodomethane262 6-(4-Fluorophenyl)-4-(2-phenyl)ethyl- Example 176 1 5.94 409.02-methyl-5-(4-pyridyl)pyrazolo[3,4- and b]pyridine iodomethane 2635-(2-Chloropyridin-4-yl)-6-(4- Example 226 1 7.30 339.2fluorophenyl)-2-methylpyrazolo[3,4- and 341.2 b]pyridine iodomethane 2644-Benzyl-6-(4-fluorophenyl)-2-methyl- Example 228 1 5.95 395.25-(4-pyridyl)pyrazolo[3,4-b]pyridine and iodomethane 2654-[6-(4-Fluorophenyl)-2-methyl-5-(4- Example 227 1 3.69 377.2pyridyl)pyrazolo[3,4-b]pyridin-4- and yl]butan-1-ol iodomethane

EXAMPLE 2664-[6-(4-Fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-4-yl]phenol

To a solution of4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(112 mg, 0.2 mmol, obtained in example 252) in EtOH (13 mL), 10% Pd/C(20 mg) was added and it was hydrogenated under atmospheric pressure atroom temperature for 2 days. It was filtered through celite, washed withEtOH and concentrated. The crude product obtained was purified bychromatography on silica gel using hexane-EtOAc-MeOH mixtures ofincreasing polarity as eluent, to afford 61 mg of the title compound(yield: 67%)

LC-MS (method 1): t_(R)=4.65 min; m/z=397.1 [M+H]⁺.

EXAMPLE 267N-[6-(4-Fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide

Following a similar procedure to that described in example 245, butstarting from3-amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridine(obtained in example 180) and acetyl chloride, the title compound wasobtained.

LC-MS (method 1): t_(R)=7.01 min; m/z=395.1 [M+H]⁺.

EXAMPLE 268N-[5-[2-[(Cyclopropylmethyl)amino]pyrimidin-4-yl]-6-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamidea)N-[6-(4-Fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamideandN-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide7-oxide

Following a similar procedure to that described in example 56, butstarting fromN-[6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide(obtained in example 267) and using 2 equivalents of m-chloroperbenzoicacid, the title compounds were obtained.

N-[6-(4-Fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide:LC-MS (method 1): t_(R)=5.64 min; m/z=427.1 [M+H]⁺.

N-[6-(4-Fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide7-oxide: LC-MS (method 1): t_(R)=4.44 min; m/z=443.0 [M+H]⁺.

b) Title Compound

Following a similar procedure to that described in example 208, butstarting fromN-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide(obtained in section a) and (cyclopropylmethyl)amine, the title compoundwas obtained.

LC-MS (method 1): t_(R)=6.19 min; m/z=418.1 [M+H]⁺.

EXAMPLE 2693-[6-(4-Fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-ola)6-(4-Fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-2-[3-(tetrahydropyran-2-yloxy)propyl]pyrazolo[3,4-b]pyridine

Following a similar procedure to that described in examples 6 and 7, butstarting from6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(obtained in example 171) and 2-(3-bromopropoxy)tetrahydropyran, thedesired compound was obtained.

LC-MS (method 1): t_(R)=7.19 min; m/z=499.2 [M+H]⁺.

b) Title Compound

Following a similar procedure to that described in example 91, butstarting from6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-2-[3-(tetrahydropyran-2-yloxy)propyl]pyrazolo[3,4-b]pyridine(obtained in section a), the title compound was obtained.

LC-MS (method 1): t_(R)=5.05 min; m/z=415.1 [M+H]⁺.

Following a similar procedure to that described in example 269, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS t_(R) m/z Example Compound name Starting compound Method (min)[M + H]⁺ 270 2-[4-(4-Benzyloxyphenyl)-6-(4- Example 229 and 2- 1 6.76517.2 fluorophenyl)-5-(4-pyridyl)- (2-bromoethoxy)-pyrazolo[3,4-b]pyridin-2- tetrahydropyran yl]ethanol 2713-[4-(4-Benzyloxyphenyl)-6-(4- Example 229 and 2- 1 6.91 531.2fluorophenyl)-5-(4-pyridyl)- (3-bromopropoxy)- pyrazolo[3,4-b]pyridin-2-tetrahydropyran yl]propan-1-ol 272 3-[6-(4-Fluorophenyl)-4-(5- Example220 and 2- 1 5.42 429.1 methylfuran-2-yl)-5-(4-pyridyl)-(3-bromopropoxy)- pyrazolo[3,4-b]pyridin-2- tetrahydropyranyl]propan-1-ol 273 3-[4-Cyclopropyl-6-(4- Example 219 and 2- 1 4.40389.1 fluorophenyl)-5-(4-pyridyl)- (3-bromopropoxy)-pyrazolo[3,4-b]pyridin-2- tetrahydropyran yl]propan-1-ol 2743-[4-(5-Bromothien-2-yl)-6-(4- Example 173 and 2- 1 6.25 508.9fluorophenyl)-5-(4-pyridyl)- (3-bromopropoxy)- 510.9pyrazolo[3,4-b]pyridin-2- tetrahydropyran yl]propan-1-ol 2753-[6-(4-Fluorophenyl)-4-propyl- Example 224 and 2- 1 4.90 391.25-(4-pyridyl)pyrazolo[3,4- (3-bromopropoxy)- b]pyridin-2-yl]propan-1-oltetrahydropyran 276 3-[4,6-Bis(4-fluorophenyl)-5- Example 230 and 2- 16.56 444.2 pyrimidin-4-ylpyrazolo[3,4- (3-bromopropoxy)-b]pyridin-2-yl]propan-1-ol tetrahydropyran 2773-[4-(3-Benzyloxyphenyl)-6-(4- Example 225 and 2- 1 7.03 531.3fluorophenyl)-5-(4-pyridyl)- (3-bromopropoxy)- pyrazolo[3,4-b]pyridin-2-tetrahydropyran yl]propan-1-ol 278 3-[4-Benzyl-6-(4-fluorophenyl)-5-Example 228 and 2- 1 5.27 439.2 (4-pyridyl)pyrazolo[3,4-b]pyridin-(3-bromopropoxy)- 2-yl]propan-1-ol tetrahydropyran

EXAMPLEs 279-285

Following a similar procedure to that described in example 268, butstarting from the appropriate compound and a suitable amine in eachcase, the compounds in the following table were obtained:

LC-MS Starting t_(R) m/z Example Compound name compound Amine Method(min) [M + H]⁺ 279 (1S)—N-(1-Phenylethyl)-[4-[6- Example (1S)-1- 1 9.32425.1 (4-fluorophenyl)-3-methyl- 234 Phenylethyl-1H-pyrazolo[3,4-b]pyridin-5- amine yl]pyrimidin-2-yl]amine 280N-Cyclopropylmethyl-4-[6- Example (Cyclopropyl- 2 5.54 373.2(4-fluorophenyl)-3-methyl- 234 methyl)amine 1H-pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2-yl]amine 281 1-[4-[6-(4-Fluorophenyl)-2- Example 1-Amino-1 4.73 379.2 methylpyrazolo[3,4- 253 propan-2-olb]pyridin-5-yl]pyrimidin-2- ylamino]propan-2-ol 282N-Cyclopropylmethyl-4-[6- Example (Cyclopropyl- 1 7.53 343.1[phenyl-1H-pyrazolo[3,4- 236 methyl)amine b]pyridin-5-yl]pyrimidin-2-yl]amine 283 2-[4-[6-(4-Fluorophenyl)-2- Example 2- 1 4.74 379.1methylpyrazolo[3,4- 253 Aminopropan- b]pyridin-5-yl]pyrimidin-2- 1-olylamino]propan-1-ol 284 4-[4-[6-(4-Fluorophenyl)-2- Example 4- 1 4.61393.2 methylpyrazolo[3,4- 253 Aminobutan- b]pyridin-5-yl]pyrimidin-2-1-ol ylamino]butan-1-ol 285 (1S)—N-(1-Phenylethyl)-[4-[6- Example(1S)-1- 1 8.10 393.1 phenyl-1H-pyrazolo[3,4- 236 Phenylethyl-b]pyridin-5-yl]pyrimidin-2- amine il]amine

EXAMPLEs 286-290

Following a similar procedure to that described in example 208, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS Starting m/z Example Compound name compounds Method t_(R) (min)[M + H]⁺ 286 N-(3-Methoxypropyl)-[4-[6-(3-trifluoro- Example 127 1 7.14429.1 methylphenyl)-1H-pyrazolo-[3,4- and 3-b]pyridin-5-yl]pyrimidin-2-yl]amine methoxy- propylamine 2873-[4-[6-(3-Trifluoromethylphenyl)-1H- Example 127 1 5.91 415.1pyrazolo[3,4-b]pyridin-5-yl]pyrimidin-2- and 3-amino-ylamino]propan-1-ol propan-1-ol 2883-[4-[6-(4-Fluorophenyl)-2-(3-hydroxy- Example 206 1 4.55 423.1propyl)pyrazolo[3,4-b]pyridin-5- and 3-amino-yl]pyrimidin-2-ylamino]propan-1-ol propan-1-ol 289N-Ethyl-[4-[6-(3-trifluoromethyl- Example 127 1 7.21 385.0phenyl)-1H-pyrazolo[3,4-b]pyridin-5- and yl]pyrimidin-2-yl]amineethylamine 290 N-Benzyl-[4-[6-(3-trifluoromethyl- Example 127 1 8.86447.1 phenyl)-1H-pyrazolo[3,4-b]pyridin-5- and yl]pyrimidin-2-yl]aminebenzylamine

EXAMPLE 2914-[5-[2-[(Cyclopropylmethyl)amino]pyrimidin-4-yl]-6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridin-4-yl]phenola)4-(4-Benzyloxyphenyl)-6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-2-methylpyrazolo[3,4-b]pyridine

Following a similar procedure to that described in example 56, butstarting from4-(4-benzyloxyphenyl)-6-(4-fluorophenyl)-2-methyl-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridine(obtained in example 255), the desired compound was obtained.

LC-MS (method 1): t_(R)=8.77 min; m/z=566.2 [M+H]⁺.

b)4-[6-(4-Fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-2-methylpyrazolo[3,4-b]pyridin-4-yl]phenol

Following a similar procedure to that described in example 266, butstarting from4-(4-benzyloxyphenyl)-6-(4-Fluorophenyl)-2-methyl-5-(2-methylsulfonylpyrimidin-4-yl)pyrazolo[3,4-b]pyridine(obtained in section a), the desired compound was obtained.

LC-MS (method 1): t_(R)=6.17 min; m/z=476.1 [M+H]⁺.

c) Title Compound

Following a similar procedure to that described in example 128, butstarting from4-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-2-methylpyrazolo[3,4-b]pyridin-4-yl]phenol(obtained in section b) and (cyclopropylmethyl)amine, the title compoundwas obtained.

LC-MS (method 1): t_(R)=6.62 min; m/z=467.2 [M+H]⁺.

EXAMPLEs 292-295

Following a similar procedure to that described in example 266, butstarting from the appropriate compounds in each case, the compounds inthe following table were obtained:

LC-MS Starting t_(R) m/z Example Compound name compound Method (min)[M + H]⁺ 292 4-[6-(4-Fluorophenyl)-2-(3-hydroxy- Example 271 1 4.41441.1 propyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridin-4-yl]phenol 2934-[6-(4-Fluorophenyl)-2-methyl-5- Example 257 1 5.71 398.1pyrimidin-4-yl)pyrazolo[3,4-b]pyridin-4- yl]phenol 2943-[6-(4-Fluorophenyl)-2-(3-hydroxy- Example 277 1 4.54 441.2propyl)-5-(4-pyridyl)pyrazolo[3,4- b]pyridin-4-yl]phenol 2953-[6-(4-Fluorophenyl)-2-methyl-5-(4- Example 261 1 4.74 397.0pyridyl)pyrazolo[3,4-b]pyridin-4- yl]phenol

EXAMPLE 2964,6-Bis(4-fluorophenyl)-5-(4-pyridyl)-2-(pyrrolidin-2-ylmethyl)pyrazolo[3,4-b]pyridine

To a solution of2-(1-benzylpyrrolidin-2-ylmethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine(83 mg, 0.1 mmol, obtained in example 259) in EtOH (6.9 mL), 10% Pd/C (8mg) and formic acid (0.34 mL) were added and heated a reflux for 2 h. Itwas allowed to cool and filtered through celite, washed with EtOH andconcentrated. The crude product obtained was purified by chromatographyon silica gel using hexane-EtOAc-MeOH—NH₃ of increasing polarity aseluent, to afford 40 mg of the title compound (yield: 57%)

LC-MS (method 1): t_(R)=4.98 min; m/z=468.1 [M+H]⁺.

EXAMPLE 2974-[4-[6-(4-Fluorophenyl)-2-methylpyrazolo[3,4-b]pyridin-5-yl]pyridin-2-ylamino]benzenesulfonamide

Following a similar procedure to that described in example 214, butstarting from5-(2-chloropyridin-4-yl)-6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine(obtained in example 263) and 4-aminobenzenesulfonamide, the titlecompound was obtained.

LC-MS (method 1): t_(R)=5.36 min; m/z=475.3 [M+H]⁺.

EXAMPLE 298N-[5-[2-[(Cyclopropylmethyl)amino]pyrimidin-4-yl]-6-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide7-oxide

Following a similar procedure to that described in example 208, butstarting fromN-[6-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetamide7-oxide (obtained in example 268 section a) and(cyclopropylmethyl)amine, the title compound was obtained.

LC-MS (method 1): t_(R)=5.45 min; m/z=434.2 [M+H]⁺.

EXAMPLE 299N-[6-(4-Fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isonicotinamidea) Isonicotinoyl chloride hydrochloride

A solution of isonicotinic acid (0.10 g, 0.8 mmol) and thionyl chloride(1 mL) were heated to reflux for 2 h and concentrated. The productobtained was used immediately in the following step.

b) Title Compound

In a volumetric flask,3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine(0.20 g, 0.7 mmol, obtained in example 70), isonicotinoyl chloridehydrochloride (0.12 g, 0.7 mmol, obtained in section a) and pyridine (1mL) were introduced under argon atmosphere. This was stirred at roomtemperature for 2 days. It was concentrated and the residue dissolved ina mixture of CHCl₃ and 1 N HCl. The phases were separated and theaqueous phase was extracted with CHCl₃ (×2). The aqueous phase wasbasified by slow addition of 1 N NaOH. Brine was added and extractedwith CHCl₃ and EtOAc. The organic phase was dried over Na₂SO₄ andconcentrated to dryness. The crude product obtained was purified bychromatography on silica gel using CHCl₃-MeOH mixtures of increasingpolarity as eluent, to afford 98 mg of the title compound (yield: 68%).

LC-MS (method 1): t_(R)=4.21 min; m/z=411.1 [M+H]⁺.

1. A compound selected from2-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine.4,6-bis(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine.3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-ol.4,6-bis(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine.N-methyl-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-pyrazolo[3,4-b]pyridin-2-yl]propyl]amine.2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethanol.1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-ol.3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-2-hydroxypropan-1-ol.[1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-yl]amine.4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-vinylpyrazolo[3,4-b]pyridine. 2.A compound according to claim 1 which is2-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine. 3.A compound according to claim 1 which is4,6-bis(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine.4. A compound according to claim 1 which is3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]propan-1-ol.5. A compound according to claim 1 which is4,6-bis(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine.6. A compound according to claim 1 which isN-methyl-[3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-pyrazolo[3,4-b]pyridin-2-yl]propyl]amine.7. A compound according to claim 1 which is2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethanol.8. A compound according to claim 1 which is1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-ol.9. A compound according to claim 1 which is3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]-2-hydroxypropan-1-ol.10. A compound according to claim 1 which is[1-[2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]ethyl]piperidin-4-yl]amine.11. A compound according to claim 1 which is4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-vinylpyrazolo[3,4-b]pyridine.